Antibacterial agents

ABSTRACT

Compounds of formula (I) have antibacterial activity: 
                         
wherein R represents hydrogen or 1, 2 or 3 optional substituents; W is ═C(R 1 )— or ═N—; R 1  is hydrogen or an optional substituent and R 2  is hydrogen, methyl, or fluorine; or R 1  and R 2  taken together are —CH 2 —, —CH 2 CH 2 —, —O—, or, in either orientation, —O—CH 2 — or —OCH 2 CH 2 —; R 3  is a radical of formula -(Alk 1 ) m -(Z) p -(Alk 2 ) n -Q wherein m, p and n are independently 0 or 1, provided that at least one of m, p and n is 1, Z is —O—, —S—, —S(O)—, —S(O 2 )—, —NH—, —N(CH 3 )—, —N(CH 2 CH 3 )—, —C(═O)—, —O—(C═O)—, —C(═O)—O—, or an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted divalent bicyclic heterocyclic radical having 5 to 10 ring atoms; Alk 1  and Alk 2  are optionally substituted C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene radicals, which may optionally terminate with or be interrupted by —O—, —S—, —S(O)—, —S(O 2 )—, —NH—, —N(CH 3 )—, or —N(CH 2 CH 3 )—; and Q is hydrogen, halogen, nitrile, or hydroxyl or an optionally substituted monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted bicyclic heterocyclic radical having 5 to 10 ring atoms.

CROSS REFERENCE TO RELATED APPLICATIONS:

This application is a National Stage application of co-pending PCT application PCT/GB2007/001012 filed Mar. 22, 2007, which claims the benefit of Great Britian application number 0605881.2 filed Mar. 23, 2006 and Great Britian application number 0623070.0 filed Nov. 16, 2006. These applications are incorporated herein by reference in their entireties.

This invention relates to the use of a class of substituted benzamides and pyridylamides as antibacterial agents, to novel members of that class per se, and to pharmaceutical compositions comprising such compounds.

BACKGROUND TO THE INVENTION

Many classes of antibacterial agents are known, including the penicillins and cephalosporins, tetracyclines, sulfonamides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol. The fundamental mechanisms of action of these antibacterial classes vary.

Bacterial resistance to many known antibacterials is a growing problem. Accordingly there is a continuing need in the art for alternative antibacterial agents, especially those that have mechanisms of action fundamentally different from the known classes.

Amongst the Gram-positive pathogens, such as staphylococci, streptococci, mycobacteria and enterococci, resistant strains have evolved/arisen which make them particularly difficult to eradicate. Examples of such strains are methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium. In view of the rapid emergence of multidrug-resistant bacteria, the development of antibacterial agents with novel modes of action that are effective against the growing number of resistant bacteria, particularly the vancomycin resistant enterococci and beta-lactam antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus, is of utmost importance.

Cell division has been of considerable interest to the pharmaceutical industry as a target because it comprises a group of well conserved target proteins that are all essential for the viability of a wide range of bacteria, and their activities are completely different from those of the proteins involved in cell division of mammalian cells. A number of compounds that act on components of the cell division machinery have been described (Ohashi, Y. et al. J. Bacteriol. 181, 1348-1351 (1999),

-   Jennings, L. D. et al. Bioorg Med Chem 12, 5115-5131 (2004),     Sutherland, A. G. et al. Org Biomol Chem 1, 4138-4140 (2003), -   Margalit, D. N. et al. Proc. Natl. Acad. Sci. USA 101, 11821-11826     (2004), Wang, J. et al. J. Biol. Chem. 278, 44424-44428 (2003),     White, E. L. et al. J. Antimicrob. Chemother. 50, 111-114 (2002),     Reynolds, R. C. et al. Bioorg Med Chem Lett 14, 3161-3164 (2004) and     Stokes et al. J Biol. Chem. 280, 39709-39715 (2005)). So far, most     effort has been directed at the FtsZ protein, since it has several     biochemical activities that can be assayed in vitro. Unfortunately,     most of the compounds described so far either have relatively low     potency, undesirable pharmacological properties or unknown     specificity.

BRIEF DESCRIPTION OF THE INVENTION

This invention is based on the finding that a class of substituted benzamides and pyridylamides has antibacterial activity as evidenced by inhibition of bacterial growth by members of that class. The compounds exhibit activity against strains of Gram-positive bacteria, such as staphylococci, clostridia, listeria and bacilli, for example Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus and Staphylococcus saprophyticus, Bacillus subtilis, Bacillus anthracis and Bacillus cereus. Whilst the invention is not limited by any particular hypothesis as to the mechanism of action of the compounds, it is presently believed that such activity is mediated by the compounds inhibiting cell division through binding to FtsZ.

DETAILED DESCRIPTION OF THE INVENTION

According to a broad aspect of the invention, there is provided the use of a compound which is a substituted benzamide or pyridylamide of formula (I) or a salt, hydrate, or solvate thereof, in the manufacture of a medicament for use in treating bacterial infection:

wherein

-   R represents hydrogen or 1, 2 or 3 optional substituents; -   W is ═C(R₁)— or ═N—; -   R₁ is hydrogen or an optional substituent and R₂ is methyl, hydrogen     or fluorine; or R₁ and -   R₂ taken together are —CH₂—, —CH₂CH₂—, —O—, or, in either     orientation, —O—CH₂—, —OCH₂CH₂—; -   R₃ is a radical of formula -(Alk¹)_(m)-(Z)_(p)-(Alk²)_(n)-Q wherein     -   m, p and n are independently 0 or 1, provided that at least one         of m, p and n is 1, -   Z is —O—, —S—, —S(O)—, —S(O₂)—, —NH—, —N(CH₃)—, —N(CH₂CH₃)—,     —C(═O)—, —O—, —(C═O)—, —C(═O)—O—, or an optionally substituted     divalent monocyclic carbocyclic or heterocyclic radical having 3 to     6 ring atoms; or an optionally substituted divalent bicyclic     heterocyclic radical having 5 to 10 ring atoms;     -   Alk¹ and Alk² are optionally substituted C₁-C₆ alkylene, C₂-C₆         alkenylene, or C₂-C₆ alkynylene radicals, which may optionally         terminate with or be interrupted by —O—, —S—, —S(O)—, —S(O₂)—,         —NH—, —N(CH₃)—, or —N(CH₂CH₃)—; and     -   Q is hydrogen, halogen, nitrile (—CN), or hydroxyl or an         optionally substituted monocyclic carbocyclic or heterocyclic         radical having 3 to 7 ring atoms; or an optionally substituted         bicyclic heterocyclic radical having 5 to 10 ring atoms.

In other broad aspects, the invention includes

-   (i) a method of treating bacterial infection in a subject suffering     such infection comprising administering to the subject an amount of     a compound (I) as defined above, sufficient to inhibit bacterial     growth; -   (ii) a method of treating bacterial contamination of a substrate     comprising applying to the site of such contamination an amount of a     compound (I) as defined above, sufficient to inhibit bacterial     growth; -   (iii) a compound (I) as defined above for use in a method of     treatment of the human body; -   (iv) a compound (I) as defined above for use in treating bacterial     infection;

Some members of the class of compounds defined by formula (I) above are believed novel in their own right, and the invention includes all such novel members of the class.

Thus the invention also includes novel compounds which are substituted benzamides or pyridylamides of formula (IC) and salts, hydrates or solvates thereof:

wherein W is ═C(R₁)— or ═N—; R₁ is hydrogen or an optional substituent and R₂ is hydrogen, methyl, or fluoro; or R₁ and R₂ taken together are —CH₂—, —CH₂CH₂—, —O— or, in either orientation, —O—CH₂— or —OCH₂CH₂—; R₄ and R₅ are independently fluoro or chloro, or one of R₄ and R₅ is hydrogen while the other is fluoro or chloro; and R₃ is a radical selected from those of the following formulae A-H, in which any vacant ring position is optionally substituted:

wherein Q is hydrogen, halogen, nitrile, or hydroxyl; or an optionally substituted monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted bicyclic heterocyclic radical having 5 to 10 ring atoms.

The invention also includes novel pyridylamide compounds of formula (ID) and salts, hydrates or solvates thereof:

wherein R₂ is hydrogen, methyl, or fluoro; and R₃ is as defined in relation to formula (IC). Terminology

As used herein, the term “(C_(a)-C_(b))alkyl” wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein the term “divalent (C_(a)-C_(b))alkylene radical” wherein a and b are integers refers to a saturated hydrocarbon chain having from a to b carbon atoms and two unsatisfied valences. The term includes, for example, methylene, ethylene, n-propylene and n-butylene.

As used herein the term “(C_(a)-C_(b))alkenyl” wherein a and b are integers refers to a straight or branched chain alkenyl moiety having from a to b carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. The term includes, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.

As used herein the term “divalent (C_(a)-C_(b))alkenylene radical” means a hydrocarbon chain having from a to b carbon atoms, at least one double bond, and two unsatisfied valences. The term includes, for example, —CH═CH— (vinylene), —CH═CH—CH₂—, —CH₂—CH═CH—, —CH═CH—CH₂—CH₂—, —CH═CH—CH₂—CH₂—CH₂—, —CH═CH—CH═CH—, —CH═CH—CH═CH—CH₂—, —CH═CH—CH═CH—CH₂—CH₂—, —CH═CH—CH₂—CH═CH—, and —CH═CH—CH₂—CH₂—CH═CH—.

As used herein the term “C_(a)-C_(b) alkynyl” wherein a and b are integers refers to straight chain or branched chain hydrocarbon groups having from a to b carbon atoms and having in addition at least one triple bond. This term would include for example, ethynyl, 1-propynyl, 1 - and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

As used herein the term “divalent (C_(a)-C_(b))alkynylene radical” wherein a and b are integers refers to a divalent hydrocarbon chain having from a to b carbon atoms, and at least one triple bond. The term includes, for example, —C≡C—, —C≡C—CH₂—, and —CH₂—C≡CH—.

As used herein the term “cycloalkyl” refers to a monocyclic or bridged monocyclic saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and bicyclo[2.2.1]hept-1-yl.

As used herein the unqualified term “aryl” refers to a mono- or bi-cyclic carbocyclic aromatic radical. Illustrative of such radicals are phenyl and naphthyl.

As used herein the unqualified term “heteroaryl” refers to a mono-, or bi-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are fused or directly linked by a covalent bond. Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, thiazolopyridinyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl and indazolyl.

As used herein the unqualified term “heterocyclyl” or “heterocyclic” includes “heteroaryl” as defined above, and in addition means a mono-, or bi-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O. Illustrative of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.

Unless otherwise specified in the context in which it occurs, the term “substituted” as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, mercapto(C₁-C₆)alkyl, (C₁-C₆)alkylthio, halo (including fluoro, bromo and chloro), fully or partially fluorinated (C₁-C₃)alkyl, (C₁-C₃)alkoxy or (C₁-C₃)alkylthio such as trifluoromethyl, trifluoromethoxy, and trifluoromethylthio, nitro, nitrile (—CN), oxo (═O), phenyl, phenoxy, monocyclic heteroaryl or heteroaryloxy with 5 or 6 ring atoms,

—COOR^(A), —COR^(A), —OCOR^(A), —SO₂R^(A), —CONR^(A)R^(B), —SO₂NR^(A)R^(B), —NR^(A)R^(B), OCONR^(A)R^(B), —NR^(B)COR^(A), —NR^(B)COOR^(A), —NR^(B)SO₂OR^(A) or —NR^(A)CONR^(A)R^(B) wherein R^(A) and R^(B) are independently hydrogen or a (C₁-C₆)alkyl group or, in the case where R^(A) and R^(B) are linked to the same N atom, R^(A) and R^(B) taken together with that nitrogen may form a cyclic amino ring. Where the substituent is phenyl, phenoxy or monocyclic heteroaryl or heteroaryloxy with 5 or 6 ring atoms, the phenyl or heteroaryl ring thereof may itself be substituted by any of the above substituents except phenyl phenoxy, heteroaryl or heteroaryloxy. An “optional substituent” or “substituent” may be one of the foregoing specified groups.

As used herein the term “salt” includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like. Those compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic acids and the like.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.

Compounds of the invention which contain one or more actual or potential chiral centres, because of the presence of asymmetric carbon atoms, can exist as a number of enantiomers or diastereoisomers with R or S stereochemistry at each chiral centre. The invention includes all such enantiomers and diastereoisomers and mixtures thereof.

ASPECTS OF THE INVENTION

A particular subclass of compounds for antibacterial use in accordance with the invention is concerned consists of those of formula (IA)

wherein R₄ and R₅ are independently fluoro or chloro, or one of R₄ and R₅ is hydrogen while the other is fluoro or chloro, and R₁, R₂ and R₃ are as defined with reference to formula (I) above.

Another particular subclass of compounds for antibacterial use in accordance with the invention is concerned consists of those of formula (IB)

wherein R₂ and R₃ are as defined with reference to formula (I) above.

In a narrow subclass of compounds for antibacterial use in accordance with the invention is concerned, including those of formula (IA) above, R₁ and R₂ are hydrogen; and in the compounds of formula (IB) above R₂ is hydrogen.

In the radical R₃, p may be 0, and m and/or n may be 1. Alternatively, p may be 1, and Z may be an optionally substituted carbocyclic or heteroaryl radical having 3 to 6 ring atoms or an optionally substituted bicyclic carbocyclic or heteroaryl radical having 5 to 10 ring atoms, which is linked to the -(Alk¹)_(m)- part of R₃ and to the -(Alk²)_(n)-Q part of R₃ via ring carbon or nitrogen atoms. Examples of divalent radicals Z in this embodiment include those selected from the following, in either orientation:

In another alternative embodiment p is 1, and Z is an optionally substituted monocyclic non-aromatic carbocyclic or heterocyclic radical having 3 to 6 ring atoms or an optionally substituted bicyclic non-aromatic carbocyclic or heterocyclic having 5 to 10 ring atoms, which is linked to the -(Alk¹)_(m)- part of R₃ and to the -(Alk²)_(n)-Q part of R₃ via ring carbon or nitrogen atoms. Examples of Z radicals, which are optionally substituted, in this embodiment include those selected from the following, in either orientation:

In the compounds with which the invention is concerned, and in any of the subclasses or embodiments of such compounds discussed above, Q may be hydrogen. However Q may also be a radical selected from any of the divalent Z radicals specifically identified above but with one of the unsatisfied valencies thereof satisfied with hydrogen or an optional substituent.

In the compounds with which the invention is concerned, and in any of the subclasses or embodiments of such compounds discussed above n and/or m may be 0.

In all compounds and classes of compounds with which the invention is concerned, it is typical that the radical R₃, when fully extended, does not exceed the length of an unbranched saturated hydrocarbon chain of 14 carbon atoms, ie does not exceed about 16 Angstroms. For example, that length may be equivalent to that of an unbranched saturated hydrocarbon chain of from 6 to 12, or 9 to 12 carbon atoms, ie from about 6 to about 14, and from about 10 to about 14 Angstroms respectively.

In the compounds with which the invention is concerned, Alk¹ and Alk², when present, may be, for example, optionally substituted straight chain C₁-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene radicals, each of which may optionally terminate with or be interrupted by —O—, —S—, —S(O)—, —S(O₂)—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—, —C(═O)—, —O—(C═O)—, —C(═O)—O—.

Any optional substituents R and any optional substituents present in Alk¹, Alk², Z and Q may be selected from, for example, methyl, —OCH₃, —CF₃, —OCF₃, ethyl, cyclopropyl, oxo, hydroxyl, —F, —Cl, —Br, cyano, acetyl, amino, methylamino, dimethylamino, acetylamino, carbamate, —CONH₂, nitro, —COOH and —CH₂OH.

Compounds of formula (IC) per se, and salts, hydrates or solvates thereof constitute a distinct aspect of the invention:

wherein W is ═C(R₁)— or ═N—;

-   R₁ is hydrogen or an optional substituent and R₂ is hydrogen,     methyl, or fluoro; or R₁ and R₂ taken together are —CH₂—, —CH₂CH₂—,     —O—, or, in either orientation, —O—CH₂— or —OCH₂CH₂—; -   R₄ and R₅ are independently fluoro or chloro, or one of R₄ and R₅ is     hydrogen while the other is fluoro or chloro; -   R₃ is a radical selected from those of the following formulae A-H,     in which any vacant ring position is optionally substituted:

wherein Q is as defined in relation to formula (I) above, and wherein any unsubstituted ring carbon is optionally substituted.

In compounds (IC) it is currently preferred that W be ═CH— and R₂ be hydrogen.

In compounds (IC) Q in radical R₃ may be hydrogen or optionally substituted phenyl.

In a particular subset of compounds (IC), R₃ is optionally substituted quinolin-2-yl, benzothiazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxadiazol-3-yl, oxadiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl or thiazolopyridin-2-yl.

Optional substituents which may be present in R₃ in the compound per se aspect of the invention include methyl, —OCH₃, —CF₃, —OCF₃, ethyl, cyclopropyl, oxo, hydroxyl, —F, —Cl, —Br, cyano, acetyl, amino, methylamino, dimethylamino, acetylamino, carbamate, —CONH₂, nitro, —COOH and —CH₂OH.

Compounds of formula (ID) per se, and salts, hydrates or solvates thereof also constitute a distinct aspect of the invention:

wherein R₂ is hydrogen, methyl, or fluoro; and R₃ is as defined in relation to formula (IC).

Specific examples of compounds with which the invention is concerned include those of the Examples herein.

There are multiple synthetic strategies for the synthesis of the compounds (I) with which the present invention is concerned, but all rely on known chemistry, known to the synthetic organic chemist. Thus, compounds according to formula (I) can be synthesised according to procedures described in the standard literature and are well-known to the one skilled in the art. Typical literature sources are “Advanced Organic Chemistry”, 4^(th) Edition (Wiley), J March, “Comprehensive Organic Transformation”, 2^(nd) Edition (Wiley), R. C. Larock, “Handbook of Heterocyclic Chemistry”, 2^(nd) Edition (Pergamon), A. R. Katritzky), review articles such as found in “Synthesis”, “Acc. Chem. Res.”, “Chem. Rev”, or primary literature sources identified by standard literature searches online or from secondary sources such as “Chemical Abstracts” or “Beilstein”.

Compounds (I) may be prepared, for example, by introduction of the radical -(Alk¹)_(m)-(Z)_(p)-(Alk²)_(n)-Q onto the hydroxyl group of a compound (II)

Further details of the synthetic approaches and schemes for the preparation of the intermediate (II) are given in the Examples herein.

As mentioned above, the compounds with which the invention are concerned are antibacterially active, since they inhibit bacterial growth. They are therefore of use in the treatment of bacterial infection in humans and non-human animals e.g. other mammals, birds and fish. The compounds include those which inhibit growth of Gram-positive organisms such as Bacillus subtilis and Staphylococcus aureus and some show activity against certain Gram-negative organisms also.

It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. As is required in the pharmaceutical art, safe and permitted doses will be determined by clinical trial, but daily dosages can vary within wide limits and will be adjusted to the individual requirements in each particular case. Typically, however, the dosage adopted for each route of administration when a compound is administered alone to adult humans is 0.0001 to 150 mg/kg body weight. Such a dosage may be given, for example, from 1 to 5 times daily. For intravenous injection a suitable daily dose is from 0.0001 to 150 mg/kg body weight. A daily dosage can be administered as a single dosage or according to a divided dose schedule.

The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties, such as oral, topical, or sterile parenteral solutions or suspensions. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.

For topical application to the eye, the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.

The active ingredient may also be administered parenterally in a sterile medium, either subcutaneously, or intravenously, or intramuscularly, or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.

Since the compounds with which the invention is concerned are antibacterially active and inhibit bacterial growth, they are also of use in treating bacterial contamination of a substrate, such as hospital instruments or work surfaces. In order to treat a contaminated substrate, the compounds may be applied to the site of such contamination in an amount sufficient to inhibit bacterial growth.

The following examples illustrate the synthesis of compounds with which the invention is concerned.

Analytical Method

The analytical methods used to characterise compounds included HPLC-MS and ¹H NMR.

HPLC-MS Conditions—Method 1

Mobile Phase: A = Acetonitrile B = 10 mM aqueous ammonium acetate Time (mins) % A % B Gradient: 0.00 20 80 0.30 20 80 4.00 90 10 5.00 90 10 5.03 20 80 Run Time: 7 min Flow Rate: 1 ml/min Injection vol: variable dependant on sample concentration Column temperature: 40° C. Column: 50 × 4.6 mm Gemini C18; 5 μm PDA Detector: 220, 240, and 254 nm analysed

HPLC-MS Conditions—Method 2

Mobile Phase: A = Acetonitrile B = 10 mM aqueous ammonium acetate Time (mins) % A % B Gradient: 0.00 20 80 0.30 20 80 24.00 90 10 28.00 90 10 28.03 20 80 Run Time: 30 min Flow Rate: 1 ml/min Injection vol: variable dependant on sample concentration Column temperature: 40° C. Column: 50 × 4.6 mm Gemini C18; 5 μm PDA Detector: 220, 240, and 254 nm analysed

HPLC-MS Conditions—Method 3

Mobile Phase: A = Acetonitrile + 0.1% Trifluoroacetic acid B = Water + 0.1% Trifluoroacetic acid Time (mins) % A % B Gradient: 0.0 0 100 1.8 95 5 2.1 95 5 2.3 0 100 2.4 0 100 Run time: 2.4 min Flow rate: 1 ml/min Injection vol: 3 μl Column temperature: ambient (20° C.) Column: 50 × 2.0 mm Hypersil C18 BDS; 5 μm UV Detector Variable wavelength detector set at 215 nm

HPLC-MS Conditions—Method 4

Mobile Phase: A = Acetonitrile + 0.1% Formic acid B = Water + 0.1% Formic acid Time (mins) % A % B Gradient: 0.0 0 100 2.5 100 0 2.7 100 0 2.71 0 100 3.0 0 100 Run time: 3.5 min Flow rate: 1 ml/min Injection vol: 3 μl Column temperature: ambient (20° C.) Column: 50 × 2.1 mm Atlantis dC18; 5 μm UV Detector Variable wavelength detector set at 215 nm

HPLC Analysis Conditions—Method 5

Column Purospher Star C-18 Mobile Phase ACN: 0.1% Formic acid (FA) Time % ACN % FA Flow Mode 0.00 10.0 90.0 7.00 10.0 90.0 15.00 90.0 10.0 18.00 90.0 10.0 25.00 10.0 90.0 30.0 10.0 90.0 Flow 1.00 ml/min UV Max Variable Column Temperature 30° C. Sample preparation MeOH + DMSO + H₂O Injection volume Variable

HPLC Analysis Conditions—Method 6

Column Discovery HSC-18 Column 250 × 4.6, 5.0 μm Mobile Phase A - Acetonitrile B - 0.1% Formic acid Time A B Flow Mode 0.0 5.0 95.0 4.0 5.0 95.0 8.0 95.0 5.0 16.0 950 5.0 18.0 5 95.0 20.0 5.0 95.0 Flow 1.00 ml/min UV Max 286.0 nm Column Temperature 45.0 deg. Sample preparation Acetonitrile:Water (50:50) Injection volume Variable

HPLC Analysis Conditions—Method 7

Column Discovery HSC-18 Column 250 × 4.6, 5.0 μm Mobile Phase A - Acetonitrile B - 0.1% Formic acid Time A B Flow Mode 0.0 5.0 95.0 4.0 5.0 95.0 8.0 95.0 5.0 16.0 950 5.0 18.0 5 95.0 20.0 5.0 95.0 Flow 1.00 ml/min UV Max variable Column Temperature 45.0 deg. Sample preparation Methanol Injection volume Variable

HPLC-MS Conditions—Method 8

Mobile Phase: A = Acetonitrile + 0.1% Formic acid B = Water + 0.1% Formic acid Time (mins) % A % B Gradient: 0.0 10 90 7.0 10 90 15.0 90 10 18.0 90 10 25.0 10 90 30.0 10 90 Run time: 30.0 min Flow rate: 1 ml/min Column temperature: Ambient (25° C.) Column: 250 × 4.6 mm Xbridge dC18; 5 μm UV Detector Variable wavelength detector set at 215 nm

HPLC-MS Conditions—Method 9

Mobile Phase: A = Acetonitrile + 0.1% Formic acid B = Water + 0.1% Formic acid Time (mins) % A % B Gradient:  0.0 10 90  7.0 10 90 15.0 90 10 18.0 90 10 25.0 10 90 30.0 10 90 Run time: 30.0 min Flow rate: 1 ml/min Column temperature: ambient (25° C.) Column: 250 × 4.6 mm Purospher Star dC18; 5 μm UV Detector Variable wavelength detector set at 262 nm

NMR

¹H NMR spectra were consistent with the required structures.

Melting points were measured on a Stuart Scientific SMP10 apparatus and are uncorrected.

Yields given are not optimised.

EXPERIMENTAL PROCEDURES

General Procedure for the Conversion of a Carboxylic Acid to a Carboxylic Amide (Method A). 3-Hydroxybenzenecarboxamide.

3-Hydroxybenzoic acid (110.5 g, 0.8 mol, 1 equiv.) was suspended in toluene (500 ml) and thionyl chloride (88.0 ml, 1.2 mol, 1.5 equiv.) was added slowly, at room temperature. The solution was heated to reflux where it was maintained for 5 h. After this time, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (300 ml) and cooled in an ice-methanol bath. Concentrated aqueous ammonia solution (˜300 ml) was added slowly, dropwise and the reaction mixture was warmed slowly to room temperature where it was stirred for 16 h. The reaction mixture was concentrated in vacuo and the resulting solid was suspended in water and filtered. The collected solid was washed with additional water (×3) and then dried in vacuo to give 3-hydroxybenzamide as an off-white solid (79.9 g, 72.8%) mp 167-168° C. HPLC-MS (method 1): m/z 136 [M−H]⁻. Rt=1.21 min. ¹H NMR (d₆-DMSO) δ=9.53 (s, 1H), 7.78 (s, 1H), 7.30-7.15 (m, 4H), 6.88 (d, J=8 Hz, 1H).

General Procedure for the Alkylation of Phenols Using Alkyl Halides (Method B).

Example 1 3-Nonyloxy-benzenecarboxamide

To a solution of 3-hydroxybenzenecarboxamide (200 mg, 1.46 mmol, 1 equiv.) in DMF (3 ml) was added K₂CO₃ (302 mg, 2.19 mmol, 1.5 equiv.) and NaI (43.5 mg, 0.29 mmol, 0.2 equiv). The suspension was stirred for 5 min before n-nonyl chloride (0.32 ml, 1.61 mmol, 1.1 equiv) was introduced. The resulting mixture was warmed to 60° C. where it was maintained for 16 h. After this time, the reaction was cooled to room temperature and partitioned between EtOAc and water. The organic phase was separated, washed with additional water (×2), dried (MgSO₄), filtered and concentrated in vacuo to reveal a colourless solid. In the case of 3-n-nonyloxybenzamide this colourless solid was stirred for 5 min with MeOH (˜0.5 ml) [NB: 3-n-nonyloxybenzamide partially soluble in MeOH] and then filtered to reveal the desired compound as a colourless solid (116 mg, 30%). HPLC-MS (method 3): m/z 264 [M+H]⁺, Rt=1.80 min. ¹H NMR (d₆-DMSO) δ=7.95 (s, 1H), 7.44-7.31 (m, 4H), 7.06 (ddd, J=8 Hz, J=2 Hz, J=1 Hz, 1H), 3.99 (t, J=6.5 Hz, 2H), 1.72 (quintet, J=6.5 Hz, 2H), 1.42 (m, 2H), 1.34-1.26 (m, 10H), 0.86 (t, J=6.5 Hz, 3H).

NB 1: The final purification step was dependent on the nature of the R group. Other purification methods used in course of the library synthesis were:

-   -   1. Recrystallisation (e.g. neat MeOH, EtOAc/hexanes, CH₃CN).     -   2. Normal phase column chromatography (silica gel).     -   3. Preparative HPLC or preparative TLC.

NB 2: In the case of water soluble target compounds, the aqueous phase was concentrated in vacuo and then washed with MeOH. The methanolic fractions were concentrated in vacuo and the crude product purified by preparative HPLC.

Examples 2 to 44 (Table A)

Examples 2 to 44 were synthesised according to Method B, scheme 2

Example 2 3 4 5 Structure

HPLC-MS: 3, 180, [M + H]⁺ 3, 180, [M + H]⁺ 3, 192, [M + H]⁺ 3, 208, [M + H]⁺ method no., m/z, ion Rt (min) 1.10 1.05 1.11 1.78 Example 6 7 8 Structure

HPLC-MS: 3, 178, [M + H]⁺ 3, 194, [M + H]⁺ 3, 222, [M + H]⁺ method no., m/z, ion Rt (min) 1.03 1.63 1.48 Example 9 10 11 Structure

HPLC-MS: 3, 196, [M + H]⁺ 3, 286, [M + H]⁺ 3, 192, [M + H]⁺ method no., m/z, ion Rt (min) 1.08 1.46 1.23 Example 12 13 14 Structure

HPLC-MS: 3, 248, [M + H]⁺ 3, 208, [M + H]⁺ 3, 222, [M + H]⁺ method no., m/z, ion Rt (min) 1.59 1.38 1.48 Example 15 16 17 Structure

HPLC-MS: 3, 220, [M + H]⁺ 3, 224, [M + H]⁺ 3, 234, [M + H]⁺ method no., m/z, ion Rt (min) 1.40 1.16 1.51 Example 18 19 Structure

HPLC-MS: 3, 266, [M + H]⁺ 3, 250, [M + H]⁺ method no., m/z, ion Rt (min) 1.20 1.67 Example 20 21 22 Structure

HPLC-MS: 3, 270, [M + H]⁺ 3, 284, [M + H]⁺ 3, 236, [M + H]⁺ method no., m/z, ion Rt (min) 1.50 1.61 1.63 Example 23 24 25 Structure

HPLC-MS: 3, 279, [M + H]⁺ 3, 236, [M + H]⁺ 3, 252, [M + H]⁺ method no., m/z, ion Rt (min) 1.01 1.62 1.18 Example 26 27 28 Structure

HPLC-MS: 3, 238, [M + H]⁺ 3, 278, [M + H]⁺ 3, 262, [M + H]⁺ method no., m/z, ion Rt (min) 1.08 1.33 1.65 Example 29 30 31 Structure

HPLC-MS: 3, 242, [M + H]⁺ 3, 192, [M + H]⁺ 3, 246, [M + H]⁺ method no., m/z, ion Rt (min) 1.43 1.20 1.49 Example 32 33 34 Structure

HPLC-MS: 3, 260, [M + H]⁺ 3, 224, [M + H]⁺ 3, 260, [M + H]⁺ method no., m/z, ion Rt (min) 1.50 1.03 1.38 Example 35 Structure

HPLC-MS: 3, 272, [M + H]⁺ method no., m/z, ion Rt (min) 1.35 Example 36 37 Structure

Yield (%) 70 70 mp (° C.) 100-101 98-99 HPLC-MS: 1, 298, [M + H]⁺ 1, 280, [M + H]⁺ method no., m/z, ion Rt (min) 4.72 3.62 Example 38 39 Structure

Yield (%) 44 7 mp (° C.) 118-120 94-95 HPLC-MS: 1, 322, [M + H]⁺ 1, 263, [M + H + CH₃CN]⁺ method no., m/z, ion Rt (min) 4.41 4.16 Example 40 41 42 Structure

Yield (%) 46 56 16 mp (° C.) — 135-137 107-109 HPLC-MS: 1, 289, [M + H + CH₃CN]⁺ 1, 293, [M + H + CH₃CN]⁺ 1, 210, [M + H + CH₃CN]⁺ method no., m/z, ion Rt (min) 4.52 3.36 3.42 Example 43 44 Structure

Yield (%) 40 54 mp (° C.) 70-72 109-111 HPLC-MS: 1, 280, [M + H ]⁺ 1, 317, [M + H + CH₃CN]⁺ method no., m/z, ion Rt (min) 3.76 5.11

Table of names of product compounds; Examples 2-44:

Example Compound name 2 3-Propoxybenzenecarboxamide 3 3-Isopropoxybenzenecarboxamide 4 3-(Cyclopropylmethoxy)benzenecarboxamide 5 3-(Pentyloxy)benzenecarboxamide 6 3-(Allyloxy)benzenecarboxamide 7 3-Butoxybenzenecarboxamide 8 3-(Hexyloxy)benzenecarboxamide 9 3-(2-Methoxyethoxy)benzenecarboxamide 10 3-(4-Phenoxybutoxy)benzenecarboxamide 11 3-[(2-Methyl-2-propenyl)oxy]benzenecarboxamide 12 3-(7-Octenyloxy)benzenecarboxamide 13 3-(Isopentyloxy)benzenecarboxamide 14 3-[(4-Methylpentyl)oxy]benzenecarboxamide 15 3-(5-Hexenyloxy)benzenecarboxamide 16 3-(2-Propoxyethoxy)benzenecarboxamide 17 3-(6-Heptenyloxy)benzenecarboxamide 18 5-[3-(Aminocarbonyl)phenoxy]pentyl acetate 19 3-(Octyloxy)benzenecarboxamide 20 3-(4-Phenylbutoxy)benzenecarboxamide 21 3-[(5-Phenylpentyl)oxy]benzenecarboxamide 22 3-[(5-Methylhexyl)oxy]benzenecarboxamide 23 3-(2-Quinolinylmethoxy)benzenecarboxamide 24 3-(Heptyloxy)benzenecarboxamide 25 Ethyl 4-[3-(aminocarbonyl)phenoxy]butanoate 26 Methyl 4-[3-(aminocarbonyl)phenoxy]butanoate 27 Cyclohexyl 2-[3-(aminocarbonyl)phenoxy]acetate 28 3-(2-Cycloheptylethoxy)benzenecarboxamide 29 3-[(3-Methylbenzyl)oxy]benzenecarboxamide 30 3-[2-Butenyloxy]benzenecarboxamide 31 3-(2-Octynyloxy)benzenecarboxamide 32 3-(4-Nonynyloxy)benzenecarboxamide 33 Ethyl 2-[3-(aminocarbonyl)phenoxy]acetate 34 3-[(4-Fluorophenethyl)oxy]benzenecarboxamide 35 3-[(4-Methoxyphenethyl)oxy]benzenecarboxamide 36 3-[(6-Phenylhexyl)oxy]benzenecarboxamide 37 Ethyl 6-[3-(aminocarbonyl)phenoxy]hexanoate 38 Methyl 10-[3-(aminocarbonyl)phenoxy]decanoate 39 3-[(2-Methylpentyl)oxy]benzenecarboxamide 40 3-[(E)-3-Octenyloxy]benzenecarboxamide 41 Butyl 2-[3-(aminocarbonyl)phenoxy]acetate 42 3-(4-Hydroxybutoxy)benzenecarboxamide 43 Butyl 4-[3-(aminocarbonyl)phenoxy]butanoate 44 3-(4-Cyclohexylbutoxy)benzenecarboxamide

General Procedure for the Alkylation of Phenols Using Alcohols Via Mitsunobu Reaction (Method C).

Example 45 3-[(Z)-5-Decenyloxy]benzenecarboxamide

To a suspension of polymer-supported triphenyl phosphine (1.4 g, 3 mmol, based on a loading of 2.15 mmol/g [purchased from Argonaut], 1.5 equiv.) swollen in THF (20 ml) at room temperature was added diisopropylazodicarboxylate (0.47 ml, 2.4 mmol, 1.2 equiv.). The mixture was shaken for 5 min before 3-hydroxybenzamide (274 mg, 2 mmol, 1 equiv.), triethylamine (0.28 ml, 2 mmol, 1 equiv.) and cis-5-decenol (313 mg, 2 mmol, 1 equiv.) were added. The resulting suspension was shaken at room temperature for 16 h and then filtered. The resin was washed with additional THF (×3) and then the combined filtrate and washings were concentrated under reduced pressure, to give the crude product as a colourless semi-solid. It was purified by column chromatography on silica eluting with EtOAc/hexane (20%-40% gradient) to give the desired compound as a white solid (390 mg, 71%), mp 98-100° C. HPLC-MS (method 1): m/z 276 [M+H]⁺, Rt=5.00 min. ¹H NMR (CDCl₃) δ=7.35 (s, 1H), 7.32-7.28 (m, 2H), 7.08-7.02 (m, 1H), 6.18 (br, 2H), 5.41-5.32 (m, 2H), 3.98 (t, J=6.4 Hz, 2H), 2.12-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.34-1.28 (m, 4H), 0.88 (t, J=7.0 Hz, 3H).

NB 1: In some cases diethylazodicarboxylate (0.38 ml, 2.4 mmol, 1.2 equiv.) was used instead of diisopropylazodicarboxylate.

NB 2: In some cases unsupported triphenyl phosphine was used. In the case of phenols containing fluorine atoms, no product could be detected when using polymer-supported triphenyl phosphine and so the reactions were performed with triphenyl phosphine.

Examples 46-61 (Table B)

Examples 46 to 61 were synthesised according to Method C, scheme 3

Example 46 47 Structure

Yield (%) 34 7.5 mp (° C.) 94-96 93-94 HPLC-MS: 1, 288, [M + H]⁺ 1, 262, [M + H]⁺ method no., m/z, ion Rt (min) 4.73 4.78 Example 48 49 Structure

Yield (%) 56 — mp (° C.) 133-134 — HPLC-MS: 1, 274, [M + H]⁺ 2, 262, [M + H]⁺ method no., m/z, ion Rt (min) 4.66 14.55 Example 50 51 Structure

Yield (%) 10 14 mp (° C.) 88-90 133-135 HPLC-MS: 1, 260, [M + H]⁺ 1, 260, [M + H]⁺ method no., m/z, ion Rt (min) 4.48 4.42 Example 52 53 Structure

Yield (%) 44 60 mp (° C.) 101-102 86-87 HPLC-MS: 1, 248, [M + H]⁺ 1, 252, [M + H]⁺ method no., m/z, ion Rt (min) 4.46 3.81 Example 54 55 Structure

Yield (%) 45 — mp (° C.) 94-95 — HPLC-MS: 1, 266, [M + H]⁺ 1, 330, [M + H]⁺ method no., m/z, ion Rt (min) 4.14 5.64 Example 56 57 Structure

Yield (%) 57 33 mp (° C.) 94-95 99-100 HPLC-MS: 1, 260, [M + H]⁺ 1, 371, [M + H]⁺ method no., m/z, ion Rt (min) 4.47 4.50 Example 58 59 Structure

Yield (%) 56 13 mp (° C.) 103-104 135-136 HPLC-MS: 1, 276, [M + H]⁺ 1, 246, [M + H]⁺ method no., m/z, ion Rt (min) 5.08 4.08 Example 60 61 Structure

Yield (%) 57 64 mp (° C.) 106-108 — HPLC-MS: 1, 263, [M + H + CH₃CN]⁺ 1, 303, [M + H + CH₃CN]⁺ method no., m/z, ion Rt (min) 4.07 4.27

Table of names of product compounds; Examples 46-61:

Example Compound name 46 3-(10-Undecynyloxy)benzenecarboxamide 47 3-[(Z)-2-Nonenyloxy]benzenecarboxamide 48 3-(5-Decynyloxy)benzenecarboxamide 49 3-[(E)-2-Nonenyloxy]benzenecarboxamide 50 3-(2-Nonynyloxy)benzenecarboxamide 51 3-(3-Nonynyloxy)benzenecarboxamide 52 3-[(Z)-5-Octenyloxy]benzenecarboxamide 53 3-[2-(Pentyloxy)ethoxy]benzenecarboxamide 54 3-[2-(Hexyloxy)ethoxy]benzenecarboxamide 55 3-{[(5E)-2,6,10-Trimethyl-5,9-undecadienyl]oxy} benzenecarboxamide 56 3-[(2E,6Z)-2,6-Nonadienyloxy]benzenecarboxamide 57 3-{3-[2-(tert-Butyl)-5-(trifluoromethyl)-1,3-oxazol-4- yl]propoxy}benzenecarboxamide 58 3-[(E)-5-Decenyloxy]benzenecarboxamide 59 3-(3-Octynyloxy)benzenecarboxamide 60 3-[(3-Methylpentyl)oxy]benzenecarboxamide 61 3-[(Z)-6-Nonenyloxy]benzenecarboxamide

3-[(6-Bromohexyl)oxy]benzenecarboxamide

(Method D) K₂CO₃ (1.38 g, 10 mmol, 1 equiv.) was added to a suspension of 3-hydroxybenzamide (1.37 g, 10 mmol, 1 equiv.) in CH₃CN (100 ml). The mixture stirred for 10 min at room temperature, before 1,6-dibromo-hexane (9.76 g, 40 mmol, 4 equiv.) was added. The resulting mixture was stirred at 60° C. for 16 h. After this time, the reaction was cooled to room temperature, any undissolved solids were filtered off and the filtrate evaporated under reduced pressure to dryness. The residue was taken-up in EtOAc and water. The organic phase was separated and washed consecutively with K₂CO₃ solution, water and brine. Dried with MgSO₄ and evaporated under reduced pressure to a small volume. The precipitant solid was filtered and washed with EtOAc/pentane, to give the desired compound as a white solid (2.0 g, 67%), mp 115-117° C. HPLC-MS (method 1): m/z 300 [M]⁺, 302 [M+2H]⁺, Rt=4.08 min.

6-[3-(Aminocarbonyl)phenoxy]hexyl(triphenyl)phosphonium bromide

A mixture of 3-[(6-bromohexyl)oxy]benzenecarboxamide (2.10 g, 7 mmol, 1 equiv.) and triphenylphosphine (1.93 g, 7.35 mmol, 1.05 equiv.) in CH₃CN (30 ml) was heated under reflux for 72 h. The solvent was evaporated under reduced pressure and the residue was triturated with dry Et₂O until it solidified. The solid was filtered and dried in vacuo to give the desired compound as a white solid (4.0 g, 100%). HPLC-MS (method 1): m/z 482 [M−Br]⁺, Rt=3.65 min.

Example 62 3-{[(Z)-7-(3-Thienyl)-6-heptenyl]oxy}benzenecarboxamide

(Method E) To a stirred suspension of 6-[3-(aminocarbonyl)phenoxy]hexyl(triphenyl)phosphonium bromide (2.0 g, 3.55 mmol, 1.2 equiv.) in anhydrous toluene (28 ml) was added a solution of potassium bis(trimethylsilyl)amide (0.5M; 7.1 ml, 3.55 mmol, 1.2 equiv.) in toluene, slowly, dropwise over a period of 15 min at 0° C., under N₂. The dark orange solution was stirred for another 20 min at 0° C. and cooled to −78° C., when thiophene-3-carboxaldehyde was instantly added, and the temperature was left to rise—from −78° C. to r.t. The light yellow mixture was stirred at r.t. for 16 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (20 ml) and the solvent was evaporated under reduced pressure. The residue was taken-up in CH₂Cl₂ and H₂O, the organic phase was separated, washed with brine and dried (Na₂SO₄). The solved was evaporated under reduced pressure and the residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-50% gradient) to give the desired compound as an off-white solid (300 mg, 35%), mp 71-73° C. By ¹H NMR analysis it consisted of a mixture of Z:E (90:10). HPLC-MS (method 1): m/z 316 [M+H]⁺, Rt=4.62 min.

Example 63 3-{[7-(3-Thienyl)heptyl]oxy}benzenecarboxamide

To a solution of example 62 3-{[(Z)-7-(3-Thienyl)-6-heptenyl]oxy}benzene carboxamide (260 mg, 0.82 mmol) in MeOH (8 ml), 10% Pd/C (30 mg) was added. The mixture was stirred under H₂ at r.t for 3 days. The catalyst was removed by filtration through a pad of Celite and the solvent was evaporated under reduced pressure, to a small volume. The precipitant solid was filtered and rinsed with Et₂O/pentane to give the desired compound as a white solid (130 mg, 48%), mp 97-100° C. HPLC-MS (method 1): m/z 318 [M+H]⁺, Rt=4.87 min.

Example 64 3-{[(Z)-7-(5-Chloro-2-furyl)-6-heptenyl]oxy}benzenecarboxamide

Synthesised from 6-[3-(aminocarbonyl)phenoxy]hexyl(triphenyl)phosphonium bromide according to Method E. Yield 72%, mp 53-56° C. By ¹H NMR analysis it consisted of a mixture of Z:E (81:19). HPLC-MS (method 1): m/z 334 [M+H]⁺, Rt=4.80 min.

3-[(7-Bromoheptyl)oxy]benzenecarboxamide

Synthesised according to Method D. HPLC-MS (method 1): m/z 314 [M]⁺, 316 [M+2H]⁺, Rt=4.37 min.

Example 65 3-(8-Nonynyloxy)benzenecarboxamide

(Method F) Lithium acetylide ethylenediamine complex (305 mg, 3.3 mmol, 1.1 equiv.) was placed in a three-neck flask, degassed, flushed with N₂ and suspended in DMSO (2 ml). To the stirred suspension a solution of 3-[(7-bromoheptyl)oxy]benzenecarboxamide (943 mg, 3 mmol, 1 equiv.) in DMSO (2 ml), was added, slowly, dropwise, at r.t., under N₂. The reaction mixture was stirred at r.t. for 16 h. After that time it was diluted with 1N HCl solution and extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (Na₂SO₄) and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography on silica eluting with EtOAc/hexane 20%, to give the desired compound as a white solid (100 mg, 13%), mp 82-83° C. HPLC-MS (method 1): m/z 260 [M+H]⁺, Rt=4.26 min.

3-[(7-Bromodecyl)oxy]benzenecarboxamide

Synthesised according to Method D. Yield 32%, mp 114-116° C., HPLC-MS (method 1): m/z 356 [M]⁺, 358 [M+2H]⁺, Rt=5.15 min.

Example 66 3-(11-Dodecynyloxy)benzenecarboxamide

Synthesised from 3-[(7-bromodecyl)oxy]benzenecarboxamide according to Method F; mp 106-108° C., HPLC-MS (method 1): m/z 302 [M+H]⁺, Rt=5.02 min.

10-Undecyn-1-ol

(Method G) A solution of commercially available 2-[(8-bromooctyl)oxy]tetrahydro-2H-pyran (1.0 g, 3.4 mmol, 1 equiv.) in DMSO (5 ml), was added, slowly, dropwise, at r.t., under N₂, to a stirred suspension of lithium acetylide ethylenediamine complex (350 mg, 3.8 mmol, 1.1 equiv.) in DMSO (5 ml). The reaction mixture was stirred at r.t. for 18 h and diluted with n-pentane (50 ml). The organic phase was washed with 1N HCl solution (2×20 ml) and water (2×20 ml), dried (Na₂SO₄) and evaporated to dryness under reduced pressure. The residue (colourless liquid, 570 mg, yield 70%) was dissolved in 95% EtOH (20 ml) together with p-toluenesulfonic acid (150 mg) and the mixture was heated under reflux for 2.5 h. After being cooled, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-30% gradient), to give the desired compound as a colourless oil (240 mg, overall yield 48%).

Example 67 3-(9-Decynyloxy)benzenecarboxamide

Synthesised from 3-hydroxybenzenecarboxamide and 10-undecyn-1-ol according to Method C, scheme 3; mp 111-112° C., HPLC-MS (method 1): m/z 274 [M+H]⁺, Rt=4.61 min.

2-Chloro-5-hydroxybenzenecarboxamide

Synthesised from commercially available 2-chloro-5-hydroxybenzenecarboxylic acid, according to Method A, scheme 1. Yield 28%, mp 159-161° C., HPLC-MS (method 1): m/z 170 [M−H]⁻, Rt=1.48 min.

Example 68 2-Chloro-5-(nonyloxy)benzenecarboxamide

Synthesised from 2-chloro-5-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 80%, HPLC-MS (method 1): m/z 339 [M+H+CH₃CN]⁺, Rt=5.29 min.

Example 69 2-Chloro-5-(10-undecynyloxy)benzenecarboxamide

Synthesised from 2-chloro-5-hydroxybenzenecarboxamide according to Method C, scheme 3. Yield 13%, HPLC-MS (method 1): m/z 322 [M+H]⁺, Rt=4.94 min.

2-Fluoro-5-hydroxybenzenecarboxamide

(Method H) Boron tribromide solution (1.0 M in CH₂Cl₂, 23.6 ml, 23.6 mmol, 2 equiv.) was added slowly, dropwise to stirred solution of 2-fluoro-5-methoxybenzenecarboxamide (2.0 g, 11.8 mmol, 1 equiv.) in CH₂Cl₂ (60 ml), at r.t., under N₂. The reaction mixture was stirred at r.t. for 48 h. The solvent was removed under reduced pressure, the residue was dissolved in water (120 ml) and extracted with EtOAc (4×100 ml). The combined organic extracts were washed with water (2×100 ml), dried (Na₂SO₄) and filtered through a pad of silica gel. The filtrate was evaporated to dryness under reduced pressure, to give the desired compound as a grey solid (1.50 g, 82%).

Examples 70-75 (Table C)

Examples 70-72 were synthesised from 2-fluoro-5-hydroxybenzenecarboxamide according to Method B, scheme 2 and Examples 73-75 were synthesised from 2-fluoro-5-hydroxybenzenecarboxamide according to Method C, scheme 3.

Example 70 71 Structure

Yield (%) — 40 mp (° C.) — 78-80 HPLC-MS: 4, 282, [M + H]⁺ 1, 337, [M + H + CH₃CN]⁺ method no., m/z, ion Rt (min) 2.42 5.69 Example 72 73 Structure

Yield (%) 42 8.5 mp (° C.) 82-83 69-71 HPLC-MS: 1, 351, [M + H + CH₃CN]⁺ 1, 307, [M + H + CH₃CN]⁺ method no., m/z, ion Rt (min) 6.03 4.71 Example 74 75 Structure

Yield (%) — 8 mp (° C.) 75-76 72-74 HPLC-MS: 1, 280, [M + H]⁺ 1, 306, [M + H]⁺ method no., m/z, ion Rt (min) 5.05 4.96

Table of names of product compounds; Examples 70-75:

Example Compound name 70 2-Fluoro-5-(nonyloxy)benzenecarboxamide 71 2-Fluoro-5-(decyloxy)benzenecarboxamide 72 2-Fluoro-5-(undecyloxy)benzenecarboxamide 73 2-Fluoro-5-[(Z)-5-octenyloxy]benzenecarboxamide 74 2-Fluoro-5-[(E)-2-nonenyloxy]benzenecarboxamide 75 2-Fluoro-5-(10-undecynyloxy)benzenecarboxamide

6-Chloro-2-fluoro-3-methoxybenzenecarboxamide

Synthesised from commercially available 6-chloro-2-fluoro-3-methoxybenzenecarboxylic acid according to Method A, scheme 1. Yield 85%, mp 154-156° C., HPLC-MS (method 1): m/z 245 [M+H+CH₃CN]⁺, Rt=2.37 min.

6-Chloro-2-fluoro-3-hydroxybenzenecarboxamide

Synthesised from 6-chloro-2-fluoro-3-methoxybenzenecarboxamide according to Method H. Yield 90%.

Example 76 6-Chloro-2-fluoro-3-(nonyloxy)benzenecarboxamide

Synthesised from 6-chloro-2-fluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 73%, mp 75-77° C., HPLC-MS (method 1): m/z 316 [M+H]⁺, Rt=5.27 min.

2-Chloro-6-fluoro-3-hydroxybenzenecarboxamide

Synthesised from commercially available 2-chloro-6-fluoro-3-methoxybenzenecarboxamide, according to Method H. Yield 78%.

Example 77 2-Chloro-6-fluoro-3-(hexyloxy)benzenecarboxamide

Synthesised from 2-chloro-6-fluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 30%, mp 66-68° C., HPLC-MS (method 1): m/z 274 [M+H]⁺, Rt=2.78 min.

Example 78 2-Chloro-6-fluoro-3-(nonyloxy)benzenecarboxamide

Synthesised from 2-chloro-6-fluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 15%, mp 64-66° C., HPLC-MS (method 1): m/z 316 [M+H]⁺, Rt=5.13 min.

2,4,6-Trifluoro-3-methoxybenzenecarboxamide

Synthesised from commercially available 2,4,6-trifluoro-3-methoxybenzenecarboxylic acid, according to Method A, scheme 1. Yield 85%, mp 102° C., HPLC-MS (method 1): m/z 206 [M+H]⁺, Rt=2.40 min.

2,4,6-Trifluoro-3-hydroxybenzenecarboxamide

Synthesised from 2,4,6-trifluoro-3-methoxybenzenecarboxamide according to Method H. Yield 100%, HPLC-MS (method 1): m/z 190 [M−H]⁻, Rt=1.07 min.

Example 79 2,4,6-Trifluoro-3-(hexyloxy)benzenecarboxamide

Synthesised from 2,4,6-trifluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 54%, mp 89-90° C., HPLC-MS: m/z 276 [M+H]⁺, Rt=4.36 min.

2,4-Difluoro-3-hydroxybenzenecarboxamide

Synthesised from commercially available 2,4-difluoro-3-methoxybenzenecarboxamide according to Method H. Yield 98%, HPLC-MS (method 1): m/z 172 [M−H]⁻, Rt=1.03 min.

Example 80 2,4-Difluoro-3-(hexyloxy)benzenecarboxamide

Synthesised from 2,4-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 51%, mp 86-87° C.

2,6-Difluoro-3-methoxybenzenecarboxamide

Synthesised from commercially available 2,6-difluoro-3-methoxybenzenecarboxylic acid according to Method A, scheme 1. Yield 84%, mp 167-169° C., HPLC-MS (method 1): m/z 188 [M+H]⁺, Rt=2.00 min.

2,6-Difluoro-3-hydroxybenzenecarboxamide

Synthesised from 2,6-difluoro-3-methoxybenzenecarboxamide according to Method H. Yield 78%. HPLC-MS (method 1): m/z 172 [M−H]⁻, Rt=1.25 min

Examples 81-87 (Table D)

Examples 81-83 were synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Examples 84-88 were synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method C, scheme 3.

Example 81 82 Structure

Yield (%) 38 71 mp (° C.) 93-95 76-78 HPLC-MS: 1, 258, [M + H]⁺ 1, 300, [M + H]⁺ method no., m/z, ion Rt (min) 4.38 5.16 Example 83 84 Structure

Yield (%) 37 29 mp (° C.) 99-101 67-69 HPLC-MS: 1, 288, M + H]⁺ 1, 298, M + H]⁺ method no., m/z, ion Rt (min) 3.72 4.91 Example 85 86 Structure

Yield (%) 6.5 16 mp (° C.) 62-64 57-59 HPLC-MS: 1, 302, M + H]⁺ 1, 288, [M + H]⁺ method no., m/z, ion Rt (min) 4.18 4.65 Example 87 88 Structure

Yield (%) 16 21 mp (° C.) <40 87-89 HPLC- 1,312, [M + H]⁺ 1, 324, [M + H]⁺ MS: method no., m/z, ion Rt (min) 4.94 4.67

Table of names of product compounds; Examples 81-88:

Example Compound name 81 2,6-Difluoro-3-(hexyloxy)benzenecarboxamide 82 2,6-Difluoro-3-(nonyloxy)benzenecarboxamide 83 Butyl 2-[3-(aminocarbonyl)-2,4-difluorophenoxy]acetate 84 2,6-Difluoro-3-[(E)-2-nonenyloxy]benzenecarboxamide 85 2,6-Difluoro-3-[2-(hexyloxy)ethoxy]benzenecarboxamide 86 2,6-Difluoro-3-[(Z)-6-nonenyloxy]benzenecarboxamide 87 2,6-Difluoro-3-[(Z)-5-decenyloxy]benzenecarboxamide 88 2,6-Difluoro-3-(10-undecynyloxy)benzenecarboxamide

Methyl 2-[3-(aminocarbonyl)-2,4-difluorophenoxy]acetate

A mixture of 2,6-difluoro-3-hydroxybenzenecarboxamide (1.2 g, 7 mmol, 1 equiv.), K₂CO₃ (2.87 g, 21 mmol, 3 equiv.) and methyl bromoacetate (0.69 ml, 7.35 mmol, 1.05 equiv.) in DMF (30 ml) was stirred at r.t. for 18 h. The mixture was diluted with water and extracted with EtOAc (4×80 ml). The combined organic extracts were dried (MgSO₄) and evaporated to dryness under reduced pressure. The product was used crude on the next step. HPLC-MS (method 1): m/z 246 [M+H]⁺, Rt=2.08 min.

2-[3-(Aminocarbonyl)-2,4-difluorophenoxy]acetic acid

Methyl 2-[3-(aminocarbonyl)-2,4-difluorophenoxy]acetate (7 mmol, 1 equiv.) was added to a solution of NaOH (1 g, 25 mmol, 3.6 equiv.) in water (20 ml) and isopropyl alcohol (5 ml). The mixture was stirred under reflux for 1.5 h, diluted with water (40 ml) and extracted with CH₂Cl₂ (40 ml). The aqueous phase was acidified to pH 1 with conc. HCl solution. The precipitant solid was filtered and dried in vacuo to give the desired compound (130 mg, 8%), mp 152-153° C. HPLC-MS (method 1): m/z 312 [M−H+2CH₃CN]⁻, Rt=0.91 min.

Example 89 Hexyl 2-[3-(aminocarbonyl)-2,4-difluorophenoxy]acetate

n-Bromohexane (0.077 ml, 0.55 mmol, 1.05 equiv.) was added to a suspension of 2-[3-(aminocarbonyl)-2,4-difluorophenoxy]acetic acid (120 mg, 0.52 mmol, 1 equiv.) and K₂CO₃ (215 mg, 1.56 mmol, 3 equiv.) in DMF (3 ml) and the mixture was stirred at 70° C. for 1.5 h. After cooling at r.t., the mixture was poured into water (25 ml) and the precipitant solid was filtered and washed with water (2×20 ml). After drying, the crude solid was triturated by stirring in hexane (10 ml), filtered and washed with hexane (3×10 ml), to give the desired compound as a white solid (99 mg, 60%), mp 108° C. HPLC-MS: m/z 316 [M+H]⁺, Rt=4.09 min.

7-Octyn-1-ol

Synthesised from commercially available 2-[(8-bromohexyl)oxy]tetrahydro-2H-pyran according to Method G. Overall yield 55%, colourless oil.

7-Octynyl 2-chloroacetate

Chloroacetyl chloride (0.16 ml, 2.0 mmol, 1 equiv.) was added to a stirred solution of 7-Octyn-1-ol (300 mg, 2.4 mmol, 1.2 equiv.) in CH₂Cl₂ (6 m-) at −5° C. The reaction mixture was allowed to warm-up to r.t., were it was stirred for 4 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%) to give the desired compound as a pale yellow liquid (450 mg, 100%).

Example 90 7-Octynyl 2-[3-(aminocarbonyl)-2,4-difluorophenoxy]acetate

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 13%, mp 130-132° C., HPLC-MS (method 1): m/z 340 [M+H]⁺, Rt=3.93 min.

Example 91 3-[4-(2-Ethylcyclopropyl)butoxy]benzenecarboxamide

A solution of diethyl zinc (1.1 M in toluene, 1.84 ml, 2.02 mmol, 1 equiv.) was added to a solution of example 52 (500 mg, 2.02 mmol, 1 equiv.) in dry toluene (1 ml), at r.t., under N₂. Diiodomethane (0.244 ml, 3.03 mmol, 1.5 equiv.) was added slowly, dropwise and the reaction mixture was stirred at r.t. for 5 days. The mixture was diluted with water (40 ml) and extracted with CH₂Cl₂ (4×40 ml). The combined organic extracts were dried (MgSO₄) and the solvents were removed under reduced pressure. By HPLC-MS, the crude residue consisted of starting material (80%) and desired product (20%). The reaction was repeated in the same way, in toluene (15 ml) using diethyl zinc (1.1 M in toluene, 6.1 ml, 6.6 mmol, 3.3 equiv.) and diiodomethane (0.244 ml, 3.03 mmol, 1.5 equiv.). The reaction mixture was stirred at 50° C. for 5 days, diluted with water (80 ml) and extracted with CH₂Cl₂ (4×50 ml). The combined organic extracts were dried (MgSO₄) and the solvents were removed under reduced pressure. The residue was triturated by stirring in pentane (15 ml) and the precipitant solid was filtered and rinsed with pentane to give 196 mg of a white compound, mp 104-105° C. By HPLC-MS it consisted of starting material (65%) and the desired product (35%). HPLC-MS (method 1): m/z 303 [M+H+CH₃CN]⁺, Rt=4.83 min.

3-[(9-Hydroxynonyl)oxy]benzenecarboxamide

Synthesised according to Method B, scheme 2. Yield 75%, mp 118-120° C., HPLC-MS (method 1): m/z 280 [M+H]⁺, Rt=3.50 min.

Example 92 9-[3-(Aminocarbonyl)phenoxy]nonyl 4-methylbenzenesulfonate

Toluenesulfonyl chloride (410 mg, 2.15 mmol, 1.5 equiv.) and triethylamine (0.40 ml, 2.88 mmol, 2 equiv.) were added to a solution of 3-[(9-hydroxynonyl)oxy]benzenecarboxamide (400 mg, 1.43 mmol, 1 equiv.) in CH₂Cl₂ (4 ml) and the reaction mixture was stirred at r.t. for 6 days. Saturated NaHCO₃ solution (40 ml) was added and the mixture was extracted with CH₂Cl₂ (3×30 ml). The combined organic extracts were dried (MgSO₄) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with CH₃OH/CH₂Cl₂ (2%), to give the desired compound as white solid (428 mg, 69%), mp 78-80° C. HPLC-MS (method 1): m/z 434 [M+H]⁺, Rt=4.90 min.

Example 93 3-[(9-Cyanononyl)oxy]benzenecarboxamide

Sodium cyanide (60 mg, 1.22 mmol, 1.3 equiv.) was added to a solution of 9-[3-(aminocarbonyl)phenoxy]nonyl 4-methylbenzenesulfonate (407 mg, 0.94 mmol, 1 equiv.) in water (10 ml) and 95% EtOH (8 ml), and the reaction mixture was stirred at 75° C. for 2 days. After cooling at r.t., the mixture was diluted with water (10 ml) and extracted with CH₂Cl₂ (3×10 ml). The combined organic extracts were dried (MgSO₄) and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography on silica eluting with EtOAc/hexane (50%), to give the desired compound as white solid (57 mg, 21%), mp 96-97° C. HPLC-MS (method 1): m/z 289 [M+H]⁺, Rt=4.16 min.

2-(Nonyloxy)isonicotinonitrile

Synthesised from commercially available 2-hydroxyisonicotinonitrile according to Method B. Yield 30%, semi-solid, HPLC-MS (method 2): m/z 288 [M+H+CH₃CN]⁺, Rt=21.46 min. The reaction gave also as by-product 1-nonyl-2-oxo-1,2-dihydro-4-pyridinecarbonitrile, yield 39%, mp 46-48° C., HPLC-MS (method 1): m/z 288 [M+H+CH₃CN]⁺, Rt=4.94 min.

Example 94 2-(Nonyloxy)isonicotinamide

A solution of 2-(nonyloxy)isonicotinonitrile (250 mg, 1.0 mmol, 1 equiv.) and sodium methoxide (10 mg, 0.1 mmol, 0.1 equiv.) in dry CH₃OH (10 ml) was stirred at r.t. for 2.5 h. A solution of lithium hydroxide (24 mg, 1.0 mmol, 1 equiv.) in water (1 ml) was added and the reaction mixture was heated under reflux for 3.5 h. After cooling at r.t., the mixture was poured into water (40 ml). The precipitant solid was filtered and dried in vacuo at 50° C., to give the desired compound as a white solid (60 mg, 23%), mp 108-110° C. HPLC-MS (method 1): m/z 265 [M+H]⁺, Rt=5.08 min.

1,2-Dibromoheptane

Bromine (1.9 ml, 37.28 mmol, 1.05 equiv.) was added slowly, dropwise, to a solution of 1-heptene (5 ml, 35.5 mmol, 1 equiv.) in CCl₄ (7 ml) cooled at −10° C., under N₂. The reaction mixture was stirred at r.t. for 16 h. The solvent was removed by evaporation under reduced pressure. The residue was partitioned between CH₂Cl₂ (200 ml) and 10% aqueous sodium metabisulfate solution (200 ml). The organic phase was separated, washed with brine and dried (Na₂SO₄). It was evaporated under reduced pressure to dryness, to give the desired compound as a colourless oil (8.94 g, 98%).

3-Pentyl-2,3-dihydro-1,4-benzodioxine-6-carbonitrile and 2-pentyl-2,3-dihydro-1,4-benzodioxine-6-carbonitrile

1,2-Dibromoheptane (5.11 g, 19.8 mmol, 1.1 equiv.) was added to a mixture of di-hydroxy benzonitrile (2.43 g, 18 mmol, 1 equiv.) and K₂CO₃ (12.4 g, 90 mmol, 5 equiv.) in CH₃CN (100 ml). The reaction mixture was heated under reflux for 4 days. After cooling to r.t., the solvent was removed under reduced pressure; the residue was diluted with water (200 ml) and extracted with EtOAc (3×150 ml). The combined organic phases were washed with brine, dried (Na₂SO₄) and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica eluting with EtOAc/hexane (5%-10% gradient) to give the desired compound as a colourless oil (390 mg, 9%); mixture of two regio-isomers. HPLC-MS (method 1): m/z 230 [M−H]⁻, Rt=5.28 min.

Example 95 3-Pentyl-2,3-dihydro-1,4-benzodioxine-6-carboxamide and 2-pentyl-2,3-dihydro-1,4-benzodioxine-6-carboxamide

A mixture of regio-isomers 3-pentyl-2,3-dihydro-1,4-benzodioxine-6-carbonitrile and 2-pentyl-2,3-dihydro-1,4-benzodioxine-6-carbonitrile (50 mg, 0.22 mmol) was stirred vigorously in conc. H₂SO₄ (0.5 ml) and warmed to 40° C. Water (82 mg) was added dropwise and the mixture was stirred for 45 min at 40° C. The mixture was cooled at −5° C., and ice (25 ml) was added quickly, with vigorous stirring. The mixture stirred at r.t. for two more hours. The precipitant solid was filtered, washed with water and dried in vacuo, at 40° C. It was purified on preparative TLC plate (Analtech, 2 mm, 20×20) eluting with methyl-tert-butyl-ether, to give the desired compound as a white solid (50 mg, 93%), HPLC-MS (method 1): m/z 291 [M+H+CH₃CN]⁺, Rt=4.14 min.

Examples 96-99, 101-116, 117, 119, 122, 124, 128-134, 137-139, 142, 144-154, 156-159 and 161-163(Table E)

The compounds of Examples 96-99, 101-116, 117, 119, 122, 124, 128-134, 137-139, 142, 144-154, 156-159 and 161-163 were synthesized according to the following general procedure: To a solution of reactant (A) in anhydrous DMF (B), 2,6-difluoro-3-hydroxybenzamide (C) and potassium carbonate (D) were added. The reaction mixture was stirred at room temperature or 25° C. under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane as the eluent to provide the product compound.

TABLE E Example 96 97 Product 2,6-Difluoro-3-(5-methyl-quinolin-2- 2,6-Difluoro-3-(6-methyl-quinolin-2- ylmethoxy)-benzamide ylmethoxy)-benzamide Reaction scheme

Reactant (A) 2-Bromomethyl-5-methyl-quinoline 2-Bromomethyl-6-methyl-quinoline Quantities of A; 0.5 g, .0021 mol; 3 ml; 0.366 g, .0021 0.05 g, .0002 mol; 1 ml; 0.036 g, B; C; D mol; 0.99 g, .0072 mol .002 mol; 0.1 g, .0007 mol Stir temp/time 25° C./124 h 25° C./124 h Ethyl acetate/ 35:65 20:80 hexane ratio Yield 0.3 g, 43%, off white solid 0.039 g, 56%, white solid ¹H NMR (DMSO, 2.51 (s, 3H), 5.42 (s, 2H), 7.06 (dt, 1H, 2.51 (s, 3H), 5.42 (s, 2H), 7.06 (dt, 400 MHz, unless J = 9.2 Hz (o-coupling), J = 1.6 Hz (m- 1H, J = 9.2 Hz (o-coupling), J = 1.6 Hz otherwise coupling), 7.31 (dt, 1H, J = 9.2 Hz (o- (m-coupling), 7.31 (dt, 1H, J = 9.2 Hz specified) coupling), J = 5.2 Hz), 7.63 (d, 2H, J = 8.4 (o-coupling), J = 5.2 Hz), 7.63 (d, 2H, Hz (o-coupling), 7.76 (s, 1H), 7.87 (s, J = 8.4 Hz (o-coupling), 7.76 (s, 1H), 1H) 7.91 (d, 1H, J = 8.8 Hz (o-coupling), 7.87 (s, 1H) 7.91 (d, 1H, J = 8.8 Hz 8.16 (s, 1H), 8.34 (d, 1H, J = 8.8 Hz (o- (o-coupling), 8.16 (s, 1H), 8.34 (d, coupling) 1H, J = 8.8 Hz (o-coupling) MS-ES+ 329.05 329.05 HPLC method 5, 12.63 5, 9.59 no., Rt (min) Example 98 99 Product 2,6-Difluoro-3-(7-methoxy-quinolin-2-ylmethoxy)- 3-[4-(2-Chloro-phenyl)-thiazol-2-ylmethoxy]- benzamide 2,6-difluoro-benzamide Reaction scheme

Reactant (A) 2-Bromomethyl-7-methoxy-quinoline 2-Bromomethyl-4-(2-chloro-phenyl)-thiazole Quantities of A; 0.01 g, .00039 mol; 2 ml; 0.068 g, .00039 mol; 0.35 g, .0012 mol; 15 ml; 0.21 g, .0012 mol; B; C; D 0.188 g, .0013 mol 0.585 g, .0042 mol Stir temp/time 25° C./124 h 25° C./124 h Ethyl acetate/ 20:80 20:80 hexane ratio Yield 0.012 g, 9%, off white solid 0.80 g, 17%, yellow brown solid ¹H NMR (DMSO, 3.92 (s, 3H), 5.41 (s, 2H), 7.06 (m, 1H, J = 9.2 Hz 5.59 (s, 2H), 7.13 (dt, 1H, J = 8.8 Hz (o- 400 MHz, unless (o-coupling) J = 1.2 Hz (m-coupling), 7.25-7.32 (m, coupling), J = 2.0 Hz (m-coupling), 7.39-7.48 otherwise 2H), 7.39 (1H, J = 2.0 Hz (m-coupling), 7.51 (d, (m, 3H), 7.57-7.59 (m, 1H), 7.85-7.86 (m, 1H), specified) 1H, J = 8.4 Hz (o-coupling), 7.88 (d, 1H, J = 4.8 7.89 (broad s, 1H), 8.17 (broad s, 2H) Hz), 7.91 (broad s, 1H), 8.16 (s, 1H), 8.33 (d, 1H, J = 8.4 Hz (o-coupling) MS-ES+ 345.06 381.03 HPLC method 5, 8.73 5, 9.99 no., Rt (min) Example 101 102 Product 2,6-Difluoro-3-(3-fluoro-benzyloxy)-benzamide 3-(Biphenyl-3-ylmethoxy)-2,6-difluoro- benzamide Reaction scheme

Reactant (A) 1-Bromomethyl-3-fluoro-benzene 3-Bromomethyl-biphenyl Quantities of A; 0.188 g, .001 mol; 2 ml; 0.173 g, .001 mol; 0.485 0.25 g, .001 mol; 2 ml; 0.173 g, .001 mol; 0.5 B; C; D g, .0035 mol g, .0035 mol Stir temp/time 25° C., 24 h 25° C., 24 h Ethyl acetate/ 20:80 20:80 hexane ratio Yield 0.058 g, 18%, white solid 0.15 g, 44%, white solid ¹H NMR (DMSO, 5.21 (s, 2H), 7.07 (dt, 1H, J = 8.8 Hz (o-coupling), 5.26 (s, 2H), 7.07 (dt, 1H, J = 8.8 Hz (o- 400 MHz, unless J = 1.6 Hz (m-coupling), 7.18 (dt, 1H, J = 8.8 Hz (o- coupling), 7.31-7.36 (m, 1H), 7.39 (d, 1H, otherwise coupling), J = 2.4 Hz (m-coupling)), 7.25-7.31 (m, J = 7.2 Hz), 7.43-7.52 (m, 4H), 7.66 (t, 3H, specified) 3H), 7.43-7.49 (m, 1H), 7.86 (broad s, 1H), 8.14 J = 8.0 Hz (o-coupling), 7.74 (s, 1H), 7.85 (s, (broad s, 1H) 1H), 8.13 (broad s, 1H) MS-ES+ 282.11 340.08 HPLC method 5, 9.41 5, 10.21 no., Rt (min) Example 103 104 Product 3-(7-Methylquinolin-2-ylmethoxy)-2,6-difluoro- 2,6-Difluoro-3-(7-chloro-benzothiazol-2- benzamide ylmethoxy)-benzamide Reaction scheme

Reactant (A) 2-Bromomethyl-7-methyl-quinoline 2-Bromomethyl-7-chloro-benzothiazole Quantities of A; 0.5 g, .002 mol; 3 ml; 0.366 g, .002 mol; 0.99 g, 0.3 g, .001 mol; 3 ml; 0.198 g, .001 mol; 0.57 B; C; D .007 mol g, .004 mol Stir temp/time 25° C., 24 h 25° C., 24 h Ethyl acetate/ 35:65 30:70 hexane ratio Yield 0.3 g, 43%, off-white solid 0.02 g, 5%, light yellow solid ¹H NMR (DMSO, 2.53 (s, 3H), 5.42 (s, 2H), 7.05 (t, 1H, J = 8.8 Hz 5.73 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (o- 400 MHz, unless (o-coupling), 7.30 (dt, 1H, J = 9.2 Hz (o-coupling), coupling), J = 1.2 Hz (m-coupling), 7.41 (dt, 1H, otherwise J = 5.2 Hz), 7.47 (d, 1H, J = 8.4 Hz (o-coupling), J = 9.2 Hz (o-coupling) J = 5.2 Hz), 7.61 (dd, 2H, specified) 7.59 (d, 1H, J = 8.4 Hz (o-coupling), 7.80 (s, 1H), J = 7.6 Hz (o-coupling), 7.91 (broad s, 1H), 7.89 (d, 2H, J = 8.8 Hz (o-coupling), 8.16 (s, 1H), 8.04 (dd, 1H, J = 7.2 Hz (o-coupling), J = 1.6 Hz 8.38 (d, 1H, J = 8.4 Hz (o-coupling) (m-coupling), 8.19 (broad s, 1H) MS-ES+ 329.17 355.04 HPLC method 5,11.00 5, 9.85 no., Rt (min) Example 105 106 Product 3-[4-(4-Methoxyphenyl)thiazol-2-ylmethoxy]-2,6- 3-[4-(4-Chloro-phenyl)-th iazol-2-ylmethoxy] difluoro-benzamide 2,6-difluoro-benzamide Reaction scheme

Reactant (A) 2-Bromomethyl-4-(4-methoxy-phenyl)-thiazole 2-Bromomethyl-4-(4-chloro-phenyl)-thiazole Quantities of A; 0.085 g, .0003 mol; 2 ml; 0.052 g, .0003 mol; 0.45 g, .0015 mol; 5 ml; 0.273 g, .0015 mol; B; C; D 0.142 g, .0010 mol 0.747 g, .0055 mol Stir temp/time 25° C., 24 h 25° C., 24 h Ethyl acetate/ 40:60 40:60 hexane ratio Yield 0.048 g, 42%, white solid 0.35 g, 58%, white solid ¹H NMR (DMSO, 3.80 (s, 3H), 5.57 (s, 2H), 7.01 (d, 2H, J = 8.8 Hz), 5.59 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (o 400 MHz, unless 7.12 (m, 1H), 7.41 (m, 1H), 7.88 (broad s, 2H), coupling), J = 2.0 Hz (m-coupling), 7.41 (dt, 1H, otherwise 7.90 (s, 1H), 8.02 (s, 1H), 8.17 (s, 1H) J = 9.2 Hz (o-coupling), J = 5.2 Hz), 7.52 (d, 2H, specified) J = 8.4 (o-coupling), 7.89 (broad s, 1H), 7.99 (d, 1H, J = 8.8 Hz (o-coupling), 8.17 (broad s, 1H), 8.26 (s, 1H) MS-ES+ 377.04 381.03 HPLC method 5, 9.63 5, 10.23 no., Rt (min) Example 107 108 Product 2,6-Difluoro-3-(3- 3-(3-Carbamoyl-2,4-difluoro-phenoxymethyl)- trifluoromethoxybenzyloxy)benzamide benzoic acid methyl ester Reaction scheme

Reactant (A) 1-Bromomethyl-3-trifluoromethoxy-benzene 3-Bromomethyl-benzoic acid methyl ester Quantities of A; 0.243 g, .001 mol; 2 ml; 0.173 g, .001 mol; 0.485 0.230 g, .001 mol; 2 ml; 0.173 g, .001 mol; B; C; D g, .003 mol 0.485 g, 003 mol Stir temp/time 25° C., 24 h 25° C., 24 h Ethyl acetate/ 20:80 20:80 hexane ratio Yield 0.058 g, 18.4%, white solid 0.055 g, 18.4%, white solid ¹H NMR (DMSO, 5.25 (s, 2H), 7.09 (dt, 1H, J = 8.8 Hz (o-coupling), 3.87 (s, 3H), 5.28 (s, 2H), 7.08 (d, 1H, J = 9.2 400 MHz, unless J = 2.0 Hz (m-coupling), 7.29 (dt, 1H, J = 9.2 Hz (o- Hz (o-coupling), 7.27-7.33 (m, 1H), 7.58 (t, otherwise coupling), J = 5.2 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.48 1H J = 7.6 Hz (o-coupling), 7.73 (d, 1H, J = 7.6 specified) (t, 2H, J = 8.8 Hz (o-coupling), 7.S6 (t, 1H, J = 8.0 Hz (o-coupling), 7.86 (s, 1H), 7.94 (d, 1H, Hz (o-coupling), 7.86 (broad s, 1H), 8.14 (s, 1H) J = 8 0 Hz (o-coupling), 8.06 (s, 1H), 8.1S (s, 1H) MS-ES+ 348.11 322.13 HPLC method 5, 9.81 5, 9.29 no., Rt (min) Example 109 110 Product 3-(6-Methoxyquinolin-2-ylmethoxy)-2,6-difluoro- 3-(6-Chloro-quinolin-2-ylmethoxy)-2,6- benzamide difluoro-benzamide Reaction scheme

Reactant (A) 2-Bromomethyl-6-methoxy-quinoline 2-Bromomethyl-6-chloro-quinoline Quantities of A; 0.1 g, .0003 mol; 2 ml; 0.068 g, .0003 mol; 0.185 0.09 g, .00038 mol; 2 ml; 0.065 g, .00038 mol; B; C; D g, .00013 mol 0.1 g, .0007 mol Stir temp/time 25° C., 24 h 25° C., 24 h Ethyl acetate/ 35:65 35:65 hexane ratio Yield 0.045 g, 33%, yellow solid 0.02 g, 16%, white solid ¹H NMR (DMSO, 3.90 (s, 3H), 5.39 (s, 2H), 7.06 (m, 1H, J = 8.8 Hz 5.45 (s, 2H), 7.06 (dt, 1H, J = 8.8 Hz (o- 400 MHz, unless (o-coupling), J = 1.6 Hz (m-coupling), 7.32 (dt, 1H, coupling) J = 1.6 Hz (m-coupling), 7.31 (dt, 1H, otherwise J = 9.2 Hz (o-coupling), J = 5.2 Hz), 7.39-7.44 (m, J = 9.2 Hz (o-coupling), J = 5.2 Hz), 7.73 (d, 1H, specified) 2H), 7.61 (d, 1H, J = 8.4 Hz (o-coupling), 7.87 (s, J = 8.4 Hz), 7.80 (dd, 1H, J = 2.4 Hz (m- 1H) 7.92 (d, 1H, J = 9.2 Hz (o-coupling), 8.16 (s, coupling), J = 8.8 Hz (o-coupling), 7.87 (s, 1H), 1H), 8.33 (d, 1H, J = 8.4 Hz (o-coupling) 8.03 (d, 1H, J = 9.2 Hz (o-coupling), 8.16 (2H, J = 2.4 Hz (m-coupling), 8.44 (d, 1H, J = 8.8 Hz (o-coupling) MS-ES+ 345.06 349.01 HPLC method 5, 9.28 5, 9.99 no., Rt (min) Example 111 112 Product 3-(7-Chloro-quinolin-2-ylmethoxy)-2,6-difluoro- 3-(8-Chloro-quinolin-2-ylmethoxy)-2,6- benzamide difluoro-benzamide Reaction scheme

Reactant (A) 2-Bromomethyl-7-chloro-quinoline 2-Bromomethyl-8-chloro-quinoline Quantities of A; 0.068 g, .00028 mol; 2 ml; .050 g, 00028 mol; 0.1 g, .0004 mol; 2 ml; 0.0733 g, 0004 mol; B; C; D 0.139 g, .001 mol 0.175 g, .0014 mol Stir temp/time 25° C., 24 h 25° C., 24 h Ethyl acetate/ 35:65 50:50 hexane ratio Yield 0.015 g, 94%, white solid 0.038 g, 27%, white solid ¹H NMR (DMSO, 5.45 (s, 2H), 7.06 (m, 1H, J = 9.2 Hz (o-coupling) 7.38 (dt, 1H, J = 9.2 Hz (o-coupling), J = 5.2 Hz), 400 MHz, unless J = 1.6 Hz (m-coupling), 7.31 (dt, 1H, J = 9.2 Hz (o- 7.61 (t, 1H, J = 8.0 Hz (o-coupling), 7.78 (d, otherwise coupling), J = 5.2 Hz), 7.68 (dd, 1H, J = 2.0 (m- 1H, J = 8.4 Hz (o-coupling), 7.87 (broad s, 1H), specified) coupling), 8.8 Hz (o-coupling)), 7.69 (d, 1H, J = 8.4 7.98-8.03 (m, 2H), 8.16 (broad s, 1H), 8.55 (d, Hz (o-coupling), 7.87 (broad s, 1H), 8.06-8.08 (m, 1H, J = 8.8 Hz (o-coupling) 2H), 8.16 (broad s, 1H), 8.50 (d, 1H, J = 8.8 Hz (o- coupling) MS-ES+ 349.00 349.01 HPLC method 5, 10.01 5, 9.98 no., Rt (min) Example 113 114 Product 2,6-Difluoro-3-(naphthalen-2-ylmethoxy)- 2,6-Difluoro-3-(5-phenyl-benzoth iazol-2- benzamide ylmethoxy)-benzamide Reaction scheme

Reactant (A) 2-Bromomethyl-naphthalene 2-Bromomethyl-5-phenyl-benzothiazole Quantities of A; 0.5 g, .0022 mol; 5 ml; 0.391 g, .0022 mol; 1.06 0.23 g, .00075 mol; 5 ml; 0.13 g, .00075 mol; B; C; D g, .0076 mol 0.36 g, .0026 mol Stir temp/time 25° C., 24 h 25° C., 24 h Ethyl acetate/ 35:65 30:70 hexane ratio Yield 0.35 g, 49%, off white solid 0.012 g, 4%, light yellow solid ¹H NMR (DMSO, 5.36 (s, 2H), 7.07 5.73 (s, 2H), 7.11 (t, 1H, J = 9.2 Hz (o- 400 MHz, unless (dt, 1H, J = 9.2 Hz (o-coupling) J = 2.0 Hz (m- coupling), 7.36-7.43 (m, 2H), 7.51 (t, 2H, otherwise coupling), 7.34 (dt, 1H, J = 9.2 Hz (o-coupling), J = 7.6 Hz (o-coupling), 7.78-7.81 (m, 3H), 7.90 specified) J = 5.2 Hz), 7.53-7.55 (m, 2H), 7.58 (dd, 1H, J = 8.4 (broad s, 1H), 8.16 (broad s, 1H), 8.29 (d, 1H, Hz (o-coupling) J = 2.4 Hz (m- coupling), 7.86 J = 8.4 Hz (o-coupling), 8.28-8.29 (d, 1H, J = 1.6 (broad s, 1H,), 7.92-7.97 (m, 3H), 7.98 (broad s, (m-coupling) 1H) 8.143 (broad s, 1H) MS-ES+ 314.06 397.11 HPLC method 5, 9.95 5, 10.28 no., Rt (min) Example 115 116 Product 2,6-Difluoro-3-(4-pyridin-2-yl-thiazol-2- 2,6-Difluoro-3-(3-methoxybenzyloxy)- ylmethoxy)-benzamide benzamide Reaction scheme

Reactant (A) 2-(2-Bromomethyl-thiazol-4-yl)-pyridine 1-Bromomethyl-3-methoxy-benzene Quantities of A; 0.23 g, .0009 mol; 3 ml; 0.156 g, .0009 mol; 0.2 g, .001 mol; 2 ml; 0.173 g, .001 mol; 0.485 B; C; D 0.424 g, .003 mol g, .0035 mol Stir temp/time 25° C., 24 h 25° C., 24 h Ethyl acetate/ 20:80 20:80 hexane ratio Yield 0.058 g, 18%, light yellow solid 0.055 g, 18%, white solid ¹H NMR (DMSO, 3.75 (s, 3H), 5.15 (s, 2H), 6.90 (d, 1H, J = 8.0 Hz 3.75 (s, 3H), 5.15 (s, 2H), 6.90 (d, 1H, J = 8.0 400 MHz, unless (o-coupling), 7.00 (broad s, 1H), 7.05 (t, 2H, Hz (o-coupling), 7.00 (broad s, 1H), 7.05 (t, otherwise J = 8.8 Hz (a-coupling), 7.25-731 (m, 2H), 7.84 2H, J = 8.8 Hz (a-coupling), 7.25-731 (m, 2H), specified) (broad s, 1H), 8.13 (broad s, 1H) 7.84 (broad s, 1H), 8.13 (broad s, 1H) MS-ES+ 294.14 294.14 HPLC method 5, 8.29 5, 9.34 no., Rt (min) Example 117 119 Product 2,6-Difluoro-3-(5-nitro-benzothiazol-2-ylmethoxy)- 2,6-Difluoro-3-(5-methoxy-benzothiazol-2- benzamide ylmethoxy)-benzamide Reaction scheme

Reactant 2-bromomethyl-5-nitro-benzothiazole 2-bromomethyl-5-methoxy-benzothiazole (A) Quantities 0.05 g, 0.183 mmol; 2 ml; 0.031 g, 0.183 mmol; 0.045 g, 0.174 mmol; 5 ml; 0.030 g, of A; B; 0.088 g, 0.64 mmol 0.174 mmol; 0.082 g, 0.609 mmol C; D Stir temp/ 25° C., 24 h RT, overnight time Ethyl 35:65 35:65 acetate/ hexane ratio Yield 0.040 g, 67%, yellow solid 0.020 g, 33%, yellow solid ¹H NMR δ 5.77 (s, 3H), 5.42 (s, 2H), 7.12 (t, 1H, J = 8.8 Hz δ 3.84 (broad s, 3H), 5.66 (s, 2H), 7.08-7.12 (DMSO, (o-coupling), 7.42 (dt, 1H, J = 9.2 Hz (o-coupling) (m, 2H, 7.38 (dt, 1H, J = 8.4 Hz (o-coupling), 400 MHz, 7.90 (broad s, 1H), 8.18 (broad s, 1H), 8.32 (d, 7.55-7.56 (m, 1H), 7.88 (broad s, 1H,) 7.99 (d, unless 1H, J = 8.8 Hz (o-coupling), 8.46 (d, 1H, J = 9.2 Hz 3H J = 9.2 Hz (o-coupling), 8.17 (broad s, 1H) otherwise (o-coupling), 8.83 (s, 1H) specified) MS-ES+ 366.06 351.10 HPLC 5, 15.63 5, 15.69 method no., Rt (min) Example 122 124 Product 2,6-Difluoro-3-(4-phenethyl-thiazol-2-ylmethoxy)- 3-[1-(5-Ohloro-benzothiazol-2-yl)-ethoxy]-2,6- benzamide difluoro-benzamide Reaction scheme

Reactant (A) 2-bromomethyl-4-phenethyl-thiazole 2-(1-bromo-ethyl)-5-chloro-benzothiazole Quantities of 0.200 g, 0.7 mmol; 5 ml; 0.125 g, 0.7 mmol; 0.300 g, 0.3 g, 0.1 mmol; 2 ml; 0.188 g, 0.1 mol; 0.5 g, A; B; C; D 2.4 mmol 0.3 mol Stir temp/ RT, overnight 25° C., 2 h time Ethyl 35:65 35:65 acetate/ hexane ratio Yield 0.108 g, 41%, white solid 0.1 g, 25%, yellow solid ¹H NMR δ 2.98 (tt, 4H, J = 4.8 Hz), 5.48 (s, 2H), 7.08-7.15 δ 1.76 (d, 3H, J = 6.4 Hz), 6.01 (q, 1H, J = 6.4 (DMSO, 400 (m, 1H), 7.17-7.28 (m, 4H), 7.33-7.38 (m, 2H), Hz (o-coupling), 7.06 (dt, 1H, J = 8.8 Hz (o MHz, unless 7.87 (broad s, 1H), 8.16 (broad s, 1H) coupling), 7.34 (dt, 1H, J = 9.2 Hz (o-coupling, otherwise 5.2 Hz), 7.S2 (dd, 1H, J = 7.2 Hz (o-coupling), specified) 7.89 (broad s, 1H), 8.11 (s, 1H), 8.17 (d, 2H, J = 8.4 Hz (o-coupling) MS-ES+ 375.14 369.06 HPLC 5, 15.84 5, 10.5 method no., Rt (min) Example 128 129 Product 2,6-Difluoro-3-(2-fluoro-3-methyl-benzyloxy)- — benzamide Reaction scheme

Reactant 1-bromomethyl-2-fluoro-3-methyl-benzene 2-bromomethyl-5-(4-chloro-phenyl)- (A) benzothiazole Quantities 0.19 g, 1.0 mmol; 2 ml; 0.173 g, 1.0 mmol; 0.050 g, 0.147 mmol; 5 ml; 0.025 g, 0.147 of A; B; 0.483 g, 3.5 mmol mmol; 0.075 g, 0.51 7 mmol C; D Stir temp/ RT, overnight 25° C., overnight time Ethyl 35:65 35:65 acetate/ hexane ratio Yield 0.112 g, 38%, white solid 0.020 g, 54%, white solid ¹H NMR δ 2.26 (s, 3H), 5.18 (s, 2H), 7.06-7.14 (m, 2H), δ 5.72 (s, 2H), 7.11 (dt, 1H, J = 8.0 Hz (o- (DMSO, 7.29-7.37 (m, 3H) 7.85 (broad s, 1H), 8.14 coupling) & 8.4 Hz) 7.39 (m, 1H), 7.55 (d, 2H 400 MHz, (broad s, 1H) J = 8.4 Hz (o-coupling), 7.78-7.83 (m, 3H), 7.89 unless (broad s, 1H), 8.18 (broad s, 1H), 8.23 (d, 2H, otherwise J = 8.0 Hz (o-coupling), 8.30 (s, 1H) specified) MS-ES+ 296.13 431.095 HPLC 5, 11.02 5, 11.02 method no., Rt (min) Example 130 131 Product — — Reaction scheme

Reactant (A) 5-bromo-2-bromomethyl-4-o-tolyl-thiazole 5-bromo-2-bromomethyl-4-m-tolyl-thiazole Quantities of 0.5 g, 1.8 mmol; 10 ml; 0.31 3 g, 1.8 mmol; 0.70 g, 2.61 mmol; 10 ml; 0.450 g, 2.61 mmol; A; B; C; D 0.884 g, 6.5 mmol 1.2 g, 9.14 mmol Stir temp/ 25° C., overnight 25° C., overnight time Ethyl 35:65 35:65 acetate/ hexane ratio Yield 0.281 g, 44%, off white solid 0.371 g, 40%, yellow solid ¹H NMR δ 5.53 (s, 2H), 7.11 (dt, 1H, J = 8.8 Hz (o- ¹H NMR (MeOH, 400 MHz); 6 2.70 (s, 3H), (DMSO, 400 coupling), 7.38 (m, 5H), 7.89 (broad s, 1H), 8.16 5.23 (s, 2H), 6.93 (dt, 1H, J = 8.8 Hz (o- MHz, unless (broad s, 1H) coupling) & 2.0 Hz (m-coupling), 7.23 (dt, 1H, otherwise J = 4.8 Hz), 7.48 (d, 1H, J = 8.0 Hz (o-coupling), specified) 7.49 (s, 1H), 7.80-7.82 (m, 1H), 7.93 (broad s, 1H) MS-ES+ 439.09 439 & 441.08 HPLC 5, 10.56 5, 10.53 method no., Rt (min) Example 132 133 Product 2,6-Difluoro-3-(2-phenyl-oxazol-4-ylmethoxy)- 2,6-Difluoro-3-(2-thiophen-2-yl-oxazol-4- benzamide ylmethoxy)-benzamide Reaction scheme

Reactant (A) 4-bromomethyl-2-phenyl-oxazole 4-bromomethyl-2-thiophen-2-yl-oxazole Quantities of A; 0.238 g, 1.0 mmol; 2 ml; 0.173 g, 1.0 mmol; 0.218 g, 1.0 mmol; 2 ml; 0.173 g, 1.0 mmol; B; C; D 0.483 g, 3.5 mmol 0.483 g, 3.5 mmol Stir temp/time 25° C., 24 h RT, overnight Ethyl acetate/ 35:65 35:65 hexane ratio Yield 0.099 g, 30%, white solid 0.020 g, 33%, off white solid ¹H NMR (DMSO, δ 5.15 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (o- δ 5.11 (s, 2H), 7.09 (dt, 1H, J = 8.8 Hz (o- 400 MHz, unless coupling), 7.42 (dt, 1H, J = 9.2 Hz J = 5.2 Hz, (m- coupling), 7.23 (t, J = 4.8 Hz), 7.39 (dt, 1H, J = otherwise coupling), 7.55 (t, 3H, J = 3.2 Hz), 7.85 (broad s, 5.2 Hz), 7.73 (d, 1H, J = 5.2 Hz), 7.82 (d, 1H, specified) 1H), 7.98-8.00 (m, 2H), 8.13 (broad s, 1H), 8.33 J = 5.2 Hz), 7.85 (broad s, 1H), 8.13 (broad s, (s, 1H) 1H), 8.27 (s, 1H) MS-ES+ 331.1 337.1 HPLC method 5, 9.43 5, 9.21 no., Rt (min) Example 134 137 Product 2,6-Difluoro-3-(5-thiophen-2-yl-[1,2,4]oxadiazol- 3-(4-Benzyl-thiazol-2-ylmethoxy)-2,6-difluoro 3-ylmethoxy)-benzamide benzamide Reaction scheme

Reactant (A) 3-bromomethyl-5-thiophen-2-yl- 4-benzyl-2-bromomethyl-thiazole [1,2,4]oxadiazole Quantities of A; 0.245 g, 1.0 mmol; 2 ml; 0.173 g, 1.0 mmol; 0.268 g, 1 mmol; 2 ml; 0.173 g, 1 mmol; B; C; D 0.483 g, 3.5 mmol 0.483 g, 3.5 mmol Stir temp/time RT, overnight 25° C., 24 h Ethyl acetate/ 35:65 40:60 hexane ratio Yield 0.020 g, 6%, off white solid 0.126 g, 35%, white solid ¹H NMR (DMSO, δ 5.43 (s, 2H), 5.15 (s, 2H), 7.12 (dt, 1H, J = 9.2 64.06 (s, 2H), 5.45 (s, 2H), 7.07 (dt, 1H, J = 7.6 400 MHz, unless Hz (o-coupling & 1.6 Hz (m-coupling), 7.34-7.41 Hz (o-coupling), 7.18 (t, 1H, J = 6.8 Hz), 7.23- otherwise (m, 2H), 7.87 (broad s, 1H), 8.06 (d, 1H, J = 4.0), 7.36 (m, 5H), 7.37 (s, 1H), 7.86 (broad s, 1H), specified) 8.12 (d, 1H, J = 4.8 Hz), 8.16 (broad s, 1H) 8.14 (broad s, 1H) MS-ES+ 338.09 361.05 HPLC method 5, 9.2 5, 15.45 no., Rt (min) Example 138 139 Product 3-(5-Cyclopropyl-[1,3,4]thiadiazol-2-ylmethoxy)- 3-(6-Chloro-thiazolo[5,4-b]pyridin-2- 2,6-difluoro-benzamide ylmethoxy)-2,6-difluoro-benzamide Reaction scheme

Reactant (A) 2-bromomethyl-5-cyclopropyl-[1,3,4]thiadiazole 2-bromomethyl-6-chloro-thiazolo[5,4- b]pyridine Quantities of A; 0.21 9 g, 1 mmol; 2 ml; 0.173 g, 1 mmol; 0.483 g, 0.1g, 0.38 mmol; 5 ml; 0.066 g, 0.38 mmol; B; C; D 3.5 mmol 0.184 g, 1.336 mmol Stir temp/time RT, overnight RT, overnight Ethyl acetate/ 30:70 35:65 hexane ratio Yield 0.118 g, 38%, pink solid 0.030 g, 22%, yellow solid ¹H NMR (DMSO, δ 1.01-1.05 (m, 2H), 1.19-1.24 (m, 2H), 2.51-2.58 δ 5.72 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (o- 400 MHz, unless (m, 1H), 5.59 (s, 2H), 7.11 (dt, 1H, J = 9.2 Hz (o- coupling), 7.37-7.43 (m, 1H), 7.90 (broad s, otherwise coupling), 7.37 (dt, 1H, J = 9.2 Hz, (a-coupling), 1H), 8.18 (broad s, 1H), 8.68 (d, 1H, J = 2.0 specified) J = 1.2 Hz (m-coupling), 7.87 (broad s, 1H), 8.15 Hz, (m-coupling), 8.73 (d, 1H, J = 2.0 Hz, (m- (broad s, 1H) coupling) MS-ES+ 312.11 356.05 HPLC method 5, 8.79 5, 15.84 no., Rt (min) Example 142 144 Product 2,6-Difluoro-3-(5-m-tolyl-benzothiazol-2-ylmethoxy)- 2,6-Difluoro-3-(2-pyrazol-1-yl-ethoxy) benzamide benzamide Reaction scheme

Reactant (A) 2-bromomethyl-5-m-tolyl-benzothiazole 1-(2-bromo-ethyl)-1H-pyrazole Quantities of 0.160 g, 0.5 mmol; 5 ml; 0.087 g, 0.5 mmol; 0.240 g, 0.175 g, 1 mmol; 2 ml; 0.173 g 1 mmol; A; B; C; D 1.76 mmol 0.483 g 3.5 mmol Stir temp/ RT, overnight 25° C., 24 h time Ethyl 35:65 35:65 acetate/ hexane ratio Yield 0.026 g, 10%, white solid 0.112 g, 42%, yellow solid ¹H NMR δ 2.82 (s, 3H), 5.28 (s, 2H), 7.08 (dt, 1H, J = 8.8 Hz (o- δ 4.39 (d, 2H, J 4.8 Hz), 4.50 (d, 2H, (DMSO, 400 coupling, J = 1.2 Hz, (m-coupling), 7.34-7.35 (m, 1H), J = 4.8 Hz), 6.24 (m, 1H), 7.03 (dt, 1H, MHz, unless 7.47 (d, 1H, J = 7.2 Hz (o-coupling), 7.53 (t, 1H, J = 8.0 J = 1.6 Hz (m-coupling), 7.17 (dt, 1H), otherwise Hz (o-coupling), 7.71 (dd, 1H, J = 8.0 Hz (o-coupling) 7.46 (d, 1H, J = 2.0 Hz (m-coupling), specified) J = 1.2 Hz, (m-coupling), 7.7S (d, 1H, J = 8.0 Hz (o- 7.76 (d, 1H, J = 2.0 (m-coupling), 7.83 coupling), 7.8S (broad s, 2H), 8.13 (d, 2H, J = 8.4 Hz), (broad s, 1H), 8.10 (broad s, 1H) 8.18 (d, 1H, J = 1.2 Hz (m-coupling) MS-ES+ 411.17 268.13 HPLC 5, 17.10 5, 13.38 method no., Rt (min) Example 145 146 Product 3-[5-(3,5-Dimethyl-isoxazol-4-yl)- 2,6-Difluoro-3-(8-methyl-quinolin-2-ylmethoxy)- [1,2,4]oxadiazol-3-ylmethoxy]-2,6- benzamide difluoro-benzamide Reaction scheme

Reactant (A) 5-(3,5-dimethyl-isoxazol-4-yl)-3-methyl- 2-Bromomethyl-8-methyl-quinoline [1,2,4]oxadiazole Quantities of A; 0,179 g, 1.0 mmol; 2 ml; 0.173 g, 1.0 0.130 g, 0.550 mmol; 1.5 ml; 0.095 g, 0.550 mmol; B; C; D mmol; 0.483 g, 3.5 mmol 0.265 g, 1.92 mmol Stir temp/time 25° C., 24 h RT, overnight Ethyl acetate/ 40:60 35:65 hexane ratio Yield 0.098 g, 28%, white solid 0.014 g, 8%, white solid ¹H NMR (DMSO, δ 2.49 (s, 3H), 2.76 (s, 3H), 5.46 (s, 2H), δ 2.71 (s, 3H), 5.46 (s, 2H), 7.06 (dt, 1H, J = 9.2 Hz (o- 400 MHz, unless 7.11 (dt, 1H, J = 8.8 Hz (o-coupling), 7.41 coupling, J = 1.6 Hz (m-coupling), 7.36 (dt, 1H, J = 9.2 otherwise (dt, 1H, J = 9.2 Hz (o-coupling), & 5.2 Hz), Hz (o-coupling, J = 5.2 Hz), 7.51 (t, 1H, J = 7.6 Hz (o- specified) 7.86 (broad s, 1H), 8.14 (broad s, 1H) coupling), 7.65 (t, 2H, J = 7.6 Hz (o-coupling), 7.82 (d, 1H, J = 8.0 Hz (o-coupling), 7.86 (broad s, 1H), 8.15 (broad s, 1H), 8.41 (d, 1H, J = 8.0 Hz (o-coupling) MS-ES+ 351.13 329.09 HPLC method 5, 8.57 5, 10.02 no., Rt (min) Example 147 148 Product 2,6-Difluoro-3-(4-fluoro-3-methyl-benzyloxy)- 2,6-Difluoro-3-(5-methyl-benzothiazol-2- benzamide ylmethoxy)-benzamide Reaction scheme

Reactant (A) 4-bromomethyl-1-fluoro-2-methyl-benzene 2-bromomethyl-5-methyl-benzothiazole Quantities of A; 0.203 g, 1 mmol; 2 ml; 0.173 g, 1 mmol; 0.483 g, 0.06 g, 0.247 mmol; 2 ml; 0.0428 g, 0.247 B; C; D 3.5 mmol mmol; 0.1 19 g, 0.866 mmol Stir temp/time RT, overnight 25° C., 24 h Ethyl acetate/ 30:70 35:65 hexane ratio Yield 0.0973 g, 33%, white solid 0.023 g, 27%, yellow solid ¹H NMR (DMSO, δ 2.24 (s, 3H), 5.10 (s, 2H), 7.06 (dt, 1H, J = 8.8 δ 2.46 (s, 3H), 5.67 (s, 2H), 7.10 (dt, J = 8.4 Hz 400 MHz, unless Hz (o-coupling), J = 1.6 Hz (m-coupling), 7.15 (t, (o-coupling), 7.30 (d, 1H, J = 8.0 Hz (o- otherwise 1H, J = 8.4 Hz (o-coupling), 7.26-7.31 (m, 2H), coupling), 7.37 (dt, 1H, J = 5.2 Hz, J = 9.2 Hz), specified) 7.36 (d, 1H, J = 7.6 Hz (o-coupling), 7.84 (broad s, 7.83 (s, 1H), 7.88 (broad s, 1H), 8.00 (d, 1H, 1H), 8.12 (broad s, 1H) J = 8.4 Hz (o-coupling), 8.17 (broad s, 1H) MS-ES+ 296.11 335.09 HPLC method 5, 15.53 5, 15.29 no., Rt (min) Example 149 150 Product 2,6-Difluoro-3-(5-styryl-[1,2,4]oxadiazol-3- 2,6-Difluoro-3-(5-thiophen-3-yl- ylmethoxy)-benzamide [1,2,4]oxadiazol-3-ylmethoxy)-benzamide Reaction scheme

Reactant (A) 3-bromomethyl-5-styryl-[1,2,4]oxadiazole 3-bromomethyl-5-thiophen-3-yl- [1,2,4]oxadiazole Quantities of 0.265 g, 1.0 mmol; 2 ml; 0.173 g 1.0 mmol; 0.483 g 0, 245 g, 1.0 mmol; 2 ml; 0.1 73 g, 1.0 mmol; A; B; C; D 3.5 mmol 0.483 g, 3.5 mmol Stir temp/ 25° C., 24 h 25° C., 24 h time Ethyl 40:60 30:70 acetate/ hexane ratio Yield 0.089 g, 25%, white solid 0.067 g, 20%, white solid ¹H NMR δ 5.41 (s, 2H), 7.11 (dt, 1H, J = 8.4 Hz (o- δ 5.43 (s, 2H), 7.11 (dt, 1H, J = 8.8 Hz (o- (DMSO, 400 coupling), 7.35-7.47 (m, 5H), 7.78- 7.93 (m, 4H), coupling), 7.38 (dt, J = 5.2 Hz, J = 9.2 Hz), 7.70 MHz, unless 8.16 (broad s, 1H) (d, 1H, J = 5.2 Hz), 7.85-7.87 (m, 2H), 8.15 otherwise (broad s, 1H) 8.64 (t, 1H, J = 1.2) specified) MS-ES+ 358.14 338.08 HPLC 5, 9.2 5, 8.66 method no., Rt (min) Example 151 152 Product 3-(5-Bromo-quinolin-2-ylmethoxy)-2,6-difluoro- 2,6-Difluoro-3-(5-thiophen-2-yl- benzamide [1,3,4]oxadiazol-2-ylmethoxy)-benzamide Reaction scheme

Reactant (A) 5-bromo-2-bromomethyl-quinoline 2-bromomethyl-5-thiophen-2-yl- [1,3,4]oxadiazole Quantities of A; 0.300 g, 1.0 mmol; 1.5 ml; 0.173 g, 1.0 mmol; 0.245 g, 1.0 mmol; 2 ml; 0.173 g, 1.0 mmol; B; C; D 0.483 g, 3.5 mmol 0.483 g, 3.5 mmol Stir temp/time RT, overnight RT, overnight Ethyl acetate/ 35:65 30:70 hexane ratio Yield 0.086 g, 22%, white solid 0.0842 g, 25%, off white solid ¹H NMR (DMSO, δ 5.50 (s, 2H), 7.06 (dt, 1H, J = 8.4 Hz (o- δ 5.55 (s, 2H), 7.14 (dt, 1H, J = 9.2 Hz (o- 400 MHz, unless coupling), 7.30-7.31 (m, 1H), 7.73 (t, 1H, J = 8.0 coupling), 7.31 (dd, 1H, J = 4.8 Hz), 7.43 (dt, otherwise Hz), 7.83 (d, 1H, J = 8.8 Hz (o-coupling), 7.87 1H, J = 9.2 Hz, J = 5.2 Hz), 7.86 (dd, 1H, J = 4.8 specified) (broad s, 1H), 7.99 (d, 1H, J = 7.6 Hz (o- Hz), 7.88 (broad s, 1H), 7.99 (d, 1H, J = 5.2 coupling), 8.06 (d, 1H, J = 8.8 Hz (o-coupling), Hz), 8.15 (broad s, 1H) 8.16 (broad s, 1H), 8.60 (d, 1H, J = 8.8 Hz (o- coupling) MS-ES+ 393.01 338.1 HPLC method 5, 15.70 5, 8.95 no., Rt (min) Example 153 154 Product 2,6-Difluoro-3-(3-thiophen-2-yl-[1,2,4]oxadiazol-5- 3-(3-Benzyloxy-benzyloxy)-2,6-difluoro- ylmethoxy)-benzamide benzamide Reaction scheme

Reactant (A) 5-bromomethyl-3-thiophen-2-yl-[1,2,4]oxadiazole 3-benzyloxy-benzylbromide Quantities of A; 0.245 g, 1.0 mmol; 2 ml; 0.1 73 g, 1.0 mmol; 0,276 g, 1.0 mmol; 2 ml; 0.1 73 g, 1.0 mmol; B; C; D 0.483 g, 3.5 mmol 0.483 g, 3.5 mmol Stir temp/time 25° C., 24 h 25° C., 24 h Ethyl acetate/ 50:50 45:55 hexane ratio Yield 0.045 g, 13%, yellow solid 0.035 g, 10%, off white solid ¹H NMR (DMSO, δ 5.67 (s, 2H), 7.13 (dt, 1H, J = 8.8 Hz (o- δ 5.10 (s, 2H), 5.15 (s, 2H), 6.98-7.09 (m, 4H), 400 MHz, unless coupling), J = 1.6 Hz (m-coupling), 7.28 (dd, 1H, 7.22-7.28 (m, 3H), 7.39 (t, 2 H, J = 7.2, (o- otherwise J = 4.0 Hz (o-coupling), 7.38 (dt, 1H J = 9.2 Hz (o- coupling), 7.37 (d, 2H, J = 7.2 (o-coupling), specified) coupling, 5.2 Hz), 7.83 (dd, 1H, J = 3.6 Hz (o- 7.85 (broad s, 1H), 8.13 (broad s, 1H) coupling), 7.91 (broad s, 1H), 7.92 (s, 1H), 8.18 (broad s, 1H) MS-ES+ 338.13 370.17 HPLC method 5, 9.26 5, 10.18 no., Rt (min) Example 156 157 Product 3-(6-Chloro-thiazolo[5,4-c]pyridin-2-ylmethoxy)- 2,6-Difluoro-3-[5-(2-hydroxy-phenyl)- 2,6-difluoro-benzamide benzothiazol-2-ylmethoxy]-benzamide Reaction scheme

Reactant 2-bromomethyl-6-chloro-thiazolo[5,4-c]pyridine 2-(2-bromomethyl-benzothiazol-5-yl)-phenol (A) Quantities 0.050 g, 0.189 mmol; 5 ml; 0.0328 g, 0.189 mmol; 0.036 g, 0.1 mmol; 5 ml; 0.020 g, 0.11 mmol; of A; B; 0.0916 g, 0.663 mmol 0.030 g, 0.385 mmol C; D Stir temp/ 25° C., overnight 25° C., overnight time Ethyl 50:50 50:50 acetate/ hexane ratio Yield 0.012 g, 18%, yellow solid 0.005g, 10.0%, yellow solid ¹H NMR δ 5.78 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (o- δ 5.71 (s, 2H), 6.91 (t, 1H, J = 5.6 Hz), 6.97 (DMSO, coupling), 7.38-7.44 (m, 1H), 7.91 (broad s, 1H), (d, 1H, J = 8.4 Hz (o-coupling), 7.11 (dt, 1H, 400 MHz, 8.20 (broad s, 2H), 9.25 (s, 1H) J = 9.2 Hz (o-coupling), 7.20 (t, 1H, J = 7.6 Hz), unless 7.35 (d, 1H, J = 8.8 Hz (o-coupling), 7.39-7.43 otherwise (m, 1H), 7.64 (d, 1H, J = 8.8 Hz (o-coupling), specified) 7.89 (broad s, 1H), 8.13 (d, 2H, J = 8.4 Hz), 8.18 (broad s, 1H) MS-ES+ 355.9 413.01 HPLC 5, 15.25 5, 15.22 method no., Rt (min) Example 158 159 Product 3-[5-Bromo-4-(4-methoxy-phenyl)-thiazol-2- 3-[5-Bromo-4-(4-chloro-phenyl)-thiazol-2- ylmethoxy]-2,6-difluoro-benzamide ylmethoxy]-2,6-difluoro-benzamide Reaction scheme

Reactant (A) 5-Bromo-2-bromomethyl-4-(4-methoxy-phenyl)- 5-Bromo-2-bromomethyl-4-(4-chloro-phenyl)- thiazole thiazole Quantities of 1.1 g, 3.0 mmol; 10 ml; 0.524 g, 3.0 mmol; 1.46 g, 0.3511 g, 0.950 mmol; 10 ml; 0.203 g, 1.1 A; B; C; D 10.2 mmol mmol; 0.570 g, 4.1 mmol Stir temp/ 25° C., overnight 25° C., overnight time Ethyl 35:65 35:65 acetate/ hexane ratio Yield 0.140 g, 10%, off white solid 0.280 g, 60%, yellow solid

¹H NMR δ 3.81 (s, 3H), 5.54 (s, 2H), 7.06 (d, 2H, J = 8.4 Hz δ 5.55 (s, 2H), 7.13 (dt, 1H, J = 8.8 Hz (o- (DMSO, 400 (o-coupling), 7.12 (dt, 1H, J = 9.2 Hz (o-coupling), coupling), 7.40 (dt, 1H, J = 9.2 Hz (o-coupling), MHz, unless 7.40 (dt, 1H, J = 9.2 Hz (o-coupling), 7.84 (d, 2H, 7.59 (d, 2H, J = 8.4 Hz (o-coupling), 7.91 (d, otherwise J = 8.8 Hz (o-coupling), 7.89 (broad s, 1H), 8.16 2H, J = 8.4 Hz (o-coupling), 7.89 (s, 1H), 8.16 specified) (broad s, 1H) (broad s, 1H) MS-ES+ 455.08 & 457.07 459.05, 461.05 HPLC 5, 10.49 5, 11.26 method no., Rt (min) Example 161 162 Product 2,6-Difluoro-3-(3-pyrrol-1-yl-benzyloxy)- 2,6-Difluoro-3-(3-phenoxy-benzyloxy)- benzamide benzamide Reaction scheme

Reactant (A) 1-(3-Bromomethyl-phenyl)-1H-pyrrole 3-phenoxy benzyl bromide Quantities of A; 0.235 g, 1.0 mmol; 5 ml; 0.173 g, 1.0 mmol; 0.263 g, 1.0 mmol; 5 ml; 0.1 73 g, 1.0 mmol; B; C; D 0.483 g, 3.5 mmol 0.483 g, 3.5 mmol Stir temp/time 25° C., overnight 25° C., overnight Ethyl acetate/ 35:65 35:65 hexane ratio Yield 0.120 g, 35%, white solid 0.105 g, 31%, white solid ¹H NMR (DMSO, δ 5.23 (s, 2H), 6.28 (t, 2H, J = 2.0, Hz (m- δ 5.17 (s, 2H), 6.96-7.05 (m, 3H), 7.07 (d, 2H, 400 MHz, unless coupling), 7.07 (dt, 1H), 7.30 (d, 2H, J = 8.0, (o- J = 8.0 Hz), 7.16 (t, 1H, J = 7.6 Hz (o-coupling), otherwise coupling), 7.37 (t, 2H, J = 2.0 Hz (m-coupling), 7.20 (d, 1H, J = 7.6 Hz (o-coupling), 7.25 (dt, specified) 7.48 (t, 1H, J = 8.0 Hz (o-coupling), 7.56 (d, 1H, 1H, J = 9.2 Hz (o-coupling), J = 5.2 Hz), 7.38- J = 9.2 Hz (o-coupling), 7.66 (s, 1H), 7.85 (broad 7.43 (m, 3 H), 7.85 (broad s, 1H), 8.13 (broad s, 1H), 8.13 (broad s, 1H) s, 1H) MS-ES+ 329.08 356.09 HPLC method 5, 9.90 5, 10.29 no., Rt (min) Example 163 Product 2,6-Difluoro-3-(5-phenyl-isoxazol-3-ylmethoxy)- benzamide Reaction scheme

Reactant (A) 4-Bromomethyl-2-thiophen-2-yl-thiazole Quantities of A; 0.260 g, 1 mmol; 5 ml; 0.173 g,lmmol; 0.483 g, B; C; D 3.5 mmol Stir temp/time 25° C., overnight Ethyl acetate/ 35:65 hexane ratio Yield 0.105 g, 30%, white solid ¹H NMR (DMSO, δ 5.2S (s, 3H), 7.09 (t, 2H, J = 8.4 Hz (o-coupling), 400 MHz, unless 7.16-7.18 (m, 1H), 7.38 (m, 1H), 7.68 (d, 1H, otherwise J = 3.6 Hz (o-coupling), 7.74 (d, 1H, J = 4.8 Hz (o- specified) coupling), 7.8S (broad s, 1H), 8.13 (broad s, 1H) MS-ES+ 353.08 HPLC method 5, 9.02 no., Rt (min)

Example 100 3-[4-(2-Bromo-5-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide

To a solution of 3-[5-Bromo-4-(2-bromo-5-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.06 g, 0.0001 mol) in 6 ml of acetic acid was added zinc (0.06 g, 0.0001 mol). The reaction mixture was refluxed for 30 min. The reaction mixture was allowed to come at 25° C. The reaction mixture was filtered on celite bed; the product was precipitated by adding water to the filtrate. The white solid was filtered and dried (0.006 g, 12%). ¹H NMR (DMSO, 400 MHz), 3.79 (s, 3H), 5.59 (s, 2H), 6.94 (dd, 1H, J=8.8 Hz (o-coupling), J=4.0 Hz), 7.09-7.15 (m, 1H), 7.27 (d, 1H, J-4.0 Hz), 7.40-7.43 (m, 1H), 7.63 (d, 1H, J=8.8 Hz (o-coupling), 7.89 (broad s, 1H), 8.11 (s, 1H), 8.18 (s, 1H); MS ES+ (455.08 & 457.08). HPLC (method 5) Rt=10.21 min.

Example 118 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-5-propyl-thiazol-2-ylmethoxy]-benzamide

To a solution of 3-[5-allyl-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.02 mmol) in 5 ml of anhydrous methanol was added dry 50 mg of dry Pd—C. The reaction mixture was stirred at 25° C. for 12 h under hydrogen atmosphere. The reaction mixture was filtered over the bed of celite. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.02 g, 2%). ¹H NMR (DMSO-d₆, 400 MHz); δ 0.92 (t, 3H, J=7.2 Hz), 1.63-1.65 (m, 2H), 2.8 (t, 2H, J=7.6 Hz (o-coupling), 3.79 (s, 3H), 5.47 (s, 2H), 7.02 (d, 2H, J=8.8 Hz (o-coupling), 7.11 (m, 1H), 7.42 (m, 1H), 7.53 (d, 2H, J=8.8 Hz (o-coupling), 7.88 (s, 1H), 8.16 (s, 1H), 8.38 (d, 1H, J=8.4 Hz (o-coupling). MS ES+ (419.14), HPLC (method 5) Rt=16.58

Example 120 3-[5-Allyl-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide

To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.0002 mol) in 5 ml of anhydrous DMF was added Allyl tributyltin (0.072 g, 0.0002 mol) and degassed the reaction mixture for the 10 minutes. Then added tetraphenylphosphine Palladium (0) (0.025 g, 0.00002 mol). The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to rt. 100 ml of water was added into it and extracted the compound with ethyl acetate, The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using methanol/DCM (2:98) as the eluent to provide the title compound as brown solid (0.120 g, 60%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.79 (s, 3H), 5.11-5.14 (m, 1H), 5.16 (s, 1H), 5.48 (s, 2H), 5.57 (s, 1H), 5.99-6.06 (m, 1H), 7.03 (d, 2H, J=8.4 Hz (o-coupling), 7.11 (dt, 1H, J=9.2 Hz (o-coupling), 7.36-7.42 (m, 1H), 7.56 (d, 2H, J=8.8 Hz (o-coupling), 7.88 (broad s, 1H), 8.16 (broad s, 1H). MS ES+ (417.06), HPLC (method 5) Rt=16.96 min.

Example 121 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-5-pyridin-3-yl-thiazol-2-ylmethoxy]-benzamide

To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.02 mmol) in DMF:H₂O (2:1), 3-pyridine boronic acid (0.054 g, 0.04 mmol), potassium phosphate (0.056 g, 0.025 mmol) was added. The reaction mixture was degassed for 10 min and then dichlorobis [(triphenylphosphine)-Palladium (II) (0.023 g, 0.003 mmol) was added and again degassed for 10 min. The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. DMF was distilled off, after cooling to r.t., water was added into reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as yellow solid (0.050 g, 50%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.75 (s, 3H), 5.59 (s, 2H), 6.92 (d, 2H, J=8.8 Hz (o-coupling), 7.14 (dt, 1H, J=9.2 Hz (o-coupling), 7.36 (d, 2H, J=8.4 Hz (o-coupling), 7.45 (dt, 2H, J=9.2 Hz (o-coupling) J=5.2 Hz (o-coupling), 7.79 (m, 1H), 7.88 (broad s, 1H), 8.16 (broad s, 1H), 8.53 (d, 1H, J=2.0 Hz (m-coupling), 8.57 (d, 1H, J=4.8 Hz). MS ES+ (454.10), HPLC (method 5) Rt=15.26 min.

Example 123 3-(5-Bromo-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide

To a solution of 5-bromo-2-bromomethyl-benzothiazole (1.1 g, 0.358 mmol) in 5 ml of anhydrous DMF was added 2,6-difluoro-3-hydroxybenzamide (0.620 g, 0.22 mol) and potassium carbonate (1.73 g, 1.25 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. Water was added to the reaction mixture the compound was precipitated out, filtered and washed with diethylether to give the title compound as yellow solid (1.1 g, 76%). ¹H NMR (DMSO-d₆, 400 MHz): δ 5.71 (s, 2H), 7.11 (dt, 1H J=8.8 Hz (o-coupling), 7.38-7.39 (m, 1H), 7.65 (d, 1H, J=8.8 Hz (o-coupling), 7.90 (broad s, 1H), 8.13 (d, 1H, J=8.8 Hz (o-coupling), 8.18 (s, 1H), 8.26 (broad s, 1H). MS ES+ (400.9), HPLC (method 5) Rt=16.57 min.

Example 125 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-5-pyridin-2-yl-thiazol-2-ylmethoxy]-benzamide

To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.02 mmol) in 5 ml of anhydrous DMF 2-tributylstannyl pyridine (0.081 g, 0.02 mmol) was added and degassed for the 10 min. Tetrakis (triphenylphosphine) Palladium (0) (0.026 g, 0.002 mmol) was added to the reaction mixture and again degassed for 10 min. and then heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to r.t. water was added and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using ethyl acetate (40:60) as the eluent to provide the title compound as white solid (0.120 g, 60%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.80 (s, 3H), 5.55 (s, 2H), 6.99 (d, 2H, J=8.8 Hz (o-coupling), 7.12 (dt, 1H, J=8.8 Hz (o-coupling), 7.23 (d, 1H, J=8.0 Hz (o-coupling), 7.29-7.32 (m, 1H), 7.44 (d, 2H, J=8.8 Hz (o-coupling), 7.62 (m, 1H), 7.69 (dt, 1H, J=8.0 Hz (o-coupling), 7.88 (broad s, 1H), 8.17 (broad s, 1H), 8.60 (d, 1H, J=4.0 Hz), MS ES+ (454.18), HPLC (method 5) Rt=15.6 min.

Example 126 3-(5-Allyl-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide

To a solution of 3-(5-bromo-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide (0.1 g, 0.025 mol) in 5 ml of anhydrous DMF was added Allyl tributyltin (0.083 g, 0.025 mol) and degassed the reaction mixture for the 10 minutes. Tetrakis (triphenylphosphine) Palladium (0) (0.029 g, 0.0025 mol) was added and again degassed for 10 min. The reaction mixture was heated at 120° C. for 1 h under the nitrogen atmosphere, then cooled to r.t. Water was added to the reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was crystallized with ethyl acetate/hexane to give the title compound as brown solid (0.050 g, 55%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.52 (d, 2H, J=6.4 Hz), 5.07-5.13 (m, 1H) 5.68 (s, 2H) 5.98-6.05 (m, 1H), 7.10 (dt, 1H, J=8.4 Hz (o-coupling), 7.31 (d, 1H, J=8.4 Hz (o-coupling), 7.38 (dt, 1H, J=9.2 Hz (o-coupling), J=5.2 Hz), 7.83 (s, 1H), 7.89 (broad s, 1H), 8.05 (d, 1H, J=8.4 Hz (o-coupling), 8.17 (broad s, 1H) MS ES+ (361.05), HPLC (method 5) Rt=16.74 min.

Example 127 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-5-pyridin-4-yl-thiazol-2-ylmethoxy]-benzamide

To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.2 g, 0.43 mmol) in 5 ml of anhydrous DMF:H₂O (2:1) 4-pyridine boronic acid (0.108 g, 0.87 mmol), potassium phosphate (0.112 g, 0.51 mmol) was added. Then degassed the reaction mixture for the 10 minutes, and added dichlorobis [(triphenylphosphine)-palladium (II) (0.046 g, 0.06 mmol) and again degassed for 10 min. The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. DMF was distilled off, after cooling to r.t. water was added into reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.045 g, 49%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.80 (s, 3H), 5.59 (s, 2H), 6.94 (d, 2H, J=8.8 Hz (o-coupling), 7.14 (dt, 1H), 7.34 (d, 1H, J=6.0 Hz (o-coupling), 7.38 (d, 2H, J=8.8 Hz (o-coupling), 7.41-7.45 (m, 1H), 7.89 (broad s, 1H), 8.17 (s, 1H), 8.60 (dd, 1H) MS ES+ (454.12), HPLC (method 5) Rt=13.55 min.

Example 135 2,6-Difluoro-3-(5-propyl-benzothiazol-2-ylmethoxy)-benzamide

To a solution of 3-(5-allyl-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide (0.1 g, 0.27 mmol) in 5 ml of anhydrous methanol was added to 20 mg of dry Pd—C. The reaction mixture was stirred at 25° C. for 12 h under hydrogen atmosphere. The reaction mixture was filtered over the celite bed. The filtrate was evaporated to dryness under reduced pressure and the compound was crystallized with ethyl acetate/hexane to give the title compound as light yellow solid (0.014 g, 14%). ¹H NMR (DMSO-d₆, 400 MHz): δ 0.92 (t, 3H, J=7.2 Hz), 1.62-1.68 (m, 2H), 2.71, 2H, J=7.2 Hz), 5.67 (s, 2H), 7.12 (dt, 1H, J=8.8 Hz (o-coupling) J=1.6 Hz), 7.32 (d, 1H, J=8.4 (o-coupling), 7.38 (dt, 1H, J=9.2 Hz (o-coupling), J=5.2 Hz), 7.83 (s, 1H), 7.89 (broad s, 1H), 8.01 (d, 1H, J=8.4 Hz (o-coupling). 8.17 (broad s, 1H). MS ES+ (363.08), HPLC (method 5) Rt=17.64 min.

Example 136 2,6-Difluoro-3-[5-(3-hydroxy-phenyl)-benzothiazol-2-ylmethoxy]-benzamide

To a suspension of 2,6-difluoro-3-[5-(3-methoxy-phenyl)-benzothiazol-2-ylmethoxy]-benzamide (0.14 g, 0.3 mmol) in 15 ml of anhydrous DCM was added drop wise boron tribromide (0.493 g, 1.9 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 3 h under nitrogen atmosphere. To the reaction mixture 5 ml of water was added at 0° C. The compound was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using ethyl acetate (40:60) as the eluent to provide the title compound as yellow solid (0.020 g, 14%). ¹H NMR (DMSO-d₆, 400 MHz): δ 5.71 (s, 2H), 6.80 (dd, 1H, J=9.6 Hz (o-coupling), 7.11 (dt, 1H, J=8.0 Hz (o-coupling), 7.17 (dt, 1H, J=8.0 Hz (o-coupling), 7.29 (t, 1H, J=8.0 Hz (o-coupling), 7.39-7.43 (m, 1H), 7.71 (dd, 1H, J=9.6 Hz) 7.89 (broad s, 1H), 8.18-8.22 (m, 2H). MS ES+ (413.01), HPLC (method 5) Rt=14.95 min

Example 140 2,6-Difluoro-3-[5-(4-hydroxy-phenyl)-benzothiazol-2-ylmethoxy]-benzamide

Compound 2,6-difluoro-3-[5-(4-methoxy-phenyl)-benzothiazol-2-ylmethoxy]-benzamide (0.095 g, 0.223 mmol) was dissolved in 5 ml of DCM and cooled to −70° C. To this, BBr₃ (0.1 ml 0.156 mmol) was added drop wise. After complete addition, reaction mixture was stirred at r.t. for 30 min. The reaction mixture was quenched with MeOH. Reaction mixture was concentrated and purified by column chromatography to obtain (0.0025 g, 3%) compound as white solid. ¹H NMR (DMSO-d₆, 400 MHz); δ 5.70 (s, 2H), 6.88 (d, 1H, J=8.4 Hz (o-coupling), 7.10 (m, 1H), 7.41 (m, 2H), 7.60 (d, 2H, J=8.8 Hz, (o-coupling), 7.71 (d, 2H), 7.89 (broad s, 1H), 8.13-8.17 (m, 2H), 9.62 (broad s, 1 H); MS ES+ (413.0).

Example 141 3-[5-(2-Amino-phenyl)-benzothiazol-2-ylmethoxy]-2,6-difluoro-benzamide

To the solution of compound 3-(5-bromo-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide (0.3 g 0.755 mmol) in dry DMF:H₂O (5 mL: 2.5 mL), phenylamine-2-boronic acid (0.260 g, 1.5 mmol), and K₂CO₃ (0.125 g, 0.9 mmol) was added under nitrogen atmosphere at room temperature. After that reaction mixture was degassed for half an hour. Dichlorobis [(triphenylphosphine)-palladium (II) was added to the reaction mixture (0.080 g, 0.113 mmol) and again degassed for half an hour and the reaction mixture was heated at 120° C. for 2 hrs under nitrogen atmosphere. DMF was distilled off, after cooling to r.t. water was added into reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50 as the eluent to provide the title compound as yellow solid (0.025 g, 8%). ¹H NMR (DMSO-d₆, 400 MHz); δ 4.86 (broad s, 2H), 5.71 (s, 2H), 6.66 (dt, 1H, J=8.4 Hz (o-coupling), 6.78 (d, 1 H, J=7.2 Hz (o-coupling), 7.04-7.13 (m, 3H), 7.37-7.44 (m, 1H), 7.51 (dd, 1H, J=8.4 Hz (o-coupling), J=1.6 Hz (m-coupling), 7.89 (broad s, 1H), 8.00 (broad s, 1H), 8.18 (d, 2H, J=4.0 Hz); MS ES+ (412.16), HPLC (method 5) Rt=15.33 min.

Example 143 2,6-Difluoro-3-[5-(3-methoxy-phenyl)-benzothiazol-2-ylmethoxy]-benzamide

To the solution of compound 3-(5-bromo-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide (0.300 g, 0.755 mmol) in dry DMF:H₂O (5 mL: 2.5 mL), added 3-methoxyphenyl boronic acid (0.228 g, 1.5 mmol), and K₃PO₄ (0.190 g, 0.9 mmol) under the inert condition at room temperature and degassed for half an hour. Then to the reaction mixture added dichlorobis [(triphenylphosphine)-palladium (II) (0.078 g, 0.075 mmol) and again degassed for half an hour. The reaction mixture was heated at 120° C. for 2 hrs under nitrogen atmosphere. DMF was distilled off, after cooling to r.t. water was added into reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50 as the eluent to provide the title compound as white solid (0.140 g, 43%). ¹H NMR (DMSO-d₆, 400 MHz); δ 3.85 (s, 3H), 5.72 (s, 2H), 6.97 (t, 1H, J=6.8 Hz (o-coupling), 7.11 (t, 1 H, J=8.8 Hz, (o-coupling), 7.30 (broad s, 1 H), 7.34 (d, 1H, J=8.8 Hz (o-coupling), 7.40 (dd, 2H, J=8.0 Hz (o-coupling), 7.79 (d, 1H, J=8.0 Hz (o-coupling), 7.90 (broad s, 1H), 8.18 (broad s, 1H), 8.21 (d, 1H, J=8.0 Hz); MS ES+ (427.14), HPLC (method 5) Rt=16.48 min.

Example 155 2,6-Difluoro-3-[4′-(4-methoxy-phenyl)-[2,5′]bithiazolyl-2′-ylmethoxy]-benzamide

To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.2 mmol) in 5 ml of anhydrous DMF was added 2-tributylstannyl thiazole (0.071 g, 0.2 mmol) and degassed the reaction mixture for the 10 minutes. Then added tetraphenylphosphine palladium (0) (0.026 g, 0.2 mmol). The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to rt. 100 ml of water was added into it and extracted the compound with ethyl acetate, The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using ethyl acetate (40:60) as the eluent to provide the title compound as yellow solid (0.003 g, 3%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.82 (s, 3H), 5.57 (s, 2H), 7.06 (d, 1H, J=8.4 Hz (o-coupling), 7.13 (dt, 1H), 7.39-7.47 (m, 1H), 7.51 (d, 2H, J=8.4 Hz (o-coupling), 7.52-7.58 (m, 1H), 7.59-7.86 (m, 2H), 7.68 (d, 1 H, J=3.2 Hz), 7.84 (d, 1 H, J=3.2 Hz), 7.89 (broad s, 1H), 8.18 (broad s, 1H), 9.12 (s, 1H); MS ES+ (460.01), HPLC (method 5) Rt=15.64 min.

Example 160 2,6-Difluoro-3-[3-(5-methyl-2-phenyl-thiazol-4-yl)-propoxy]-benzamide

3-(5-Methyl-2-phenyl-thiazol-4-yl)-propan-1-ol

To a solution of 3-(5-methyl-2-phenyl-thiazol-4-yl)-propan-1-ol (0.219 g, 1.0 mmol) in 5 ml of anhydrous DMF, 2,6-difluoro-3-hydroxybenzamide (0.173 g, 1.0 mmol), PPh₃ (0.262 g, 1.0 mmol) and diisopropyl azodicarboxylate (0.202 g, 1.0 mmol) was added. The reaction mixture was stirred at 80° C. for overnight under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (35:65) as the eluent to provide the title compound as white solid (0.050 g, 13%). ¹H NMR (DMSO-d₆, 400 MHz): δ 2.44 (broad s, 3H), 3.14 (t, 2H, J=6.4 Hz), 4.35 (t, 2H, J=6.4 Hz), 7.04 (dt, 1H, J=9.2 Hz (o-coupling), 7.22-7.28 (m, 1H), 7.43-7.49 (m, 3H), 7.83-7.86 (m, 3H), 8.10 (s, 1H); MS ES+ (375.15), HPLC (method 5) Rt=10.67 min.

Example 164 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-[5,5′]bithiazolyl-2-ylmethoxy]-benzamide

To a solution of 2,6-difluoro-3-[4-(4-methoxy-phenyl)-[5,5′]bithiazolyl-2-ylmethoxy]-benzamide (0.100 g, 0.2 mmol) in 5 ml of anhydrous DMF, and 5-Tributylstannanyl-thiazole-2-carboxylic acid (0.091 g, 0.2 mmol) was added. The reaction mixture was stirred at 80° C. for overnight under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (35:65) as the eluent to provide the title compound as white solid (0.025 g, 25%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.78 (s, 3H), 5.57 (s, 2H), 6.97 (d, 2H, J=8.8 Hz (o-coupling), 7.13 (t, 1H), 7.44 (d, J=8.8, (o-coupling, 3H), 7.89 (broad s, 1H), 8.05 (s, 1H), 8.17 (broad s, 1H), 9.12 (s, 1H); MS ES+ (459.94), HPLC (method 5) Rt=15.21 min.

Example 165 2-Fluoro-3-Hexoxy-benzamide

To the solution of 2-fluoro-3-Hydroxy-benzamide (0.12 g, 0.774 mmol) in 20 mL DMF 1-bromohexane (0.13 mL, 1.0 mmol), Potassium Carbonate (0.213, 1.4 mmol) was added. The reaction mixture was stirred at 90° C. for 4 h. DMF was distilled off and the reaction mixture was extracted with EtOAc. The obtained crude compound was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound. (0.05 g, 28%). ¹H NMR (DMSO-d₆, 400 MHz with D₂O): δ 0.82-0.99 (m, 3H), 1.10-1.33 (m, 6H), 1.67-1.71 (m, 2H), 3.99-4.15 (t, 2H, J=8.0 Hz), 7.08-7.24 (m, 2H). MS ES+ (214.33), HPLC (method 6) Rt=11.15 min.

Example 166 2-Hydroxy-3-Hexoxy-benzamide

A mixture of 2-fluoro-3-Hexoxy-benzamide (0.30 g, 1.2 mmol), copper sulfate (0.10 g, 0.4 mol) copper (0.015 g, 0.2 mmol) and NaOH (2.5 ml) was stirred at 100° C. for 14 hrs. After completion of reaction the reaction mixture was acidified and extracted with EtOAc. The obtained crude compound was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as yellow (0.15 g, 50%). ¹H NMR (DMSO-d₆, 400 MHz with D₂O): δ 3.9 (s, 3H), 7.11-7.18 (m, 2H), 7.53-7.58 (m, 1H). MS ES+ (229.0 M+2H adduct). HPLC (Method 7) Rt=11.16 min.

Example 167 Synthesis of 3-Fluoro-5-hexyloxy benzamide

To a solution of 3-amino-5-hexyloxy benzamide (0.9 g, 3.8 mmol) in tetrafluoroboric acid (20 ml), a solution of sodium nitrite (0.315 mg, 4.6 mmol) in water (5 ml) was added at 0° C. and stirred for 1 hr. Later it was allowed to come to RT and stirred for 1 hr followed by heating at 60° C. for 2 hrs. It was then basify to pH=14 using saturated NaOH solution and extracted with dichloromethane (3×30 ml). The solvent was evaporated to yield crude product, which was purified by column chromatography using silica gel (230-400 mesh) and dichloromethane as an eluent (100 mg, 11%). ¹H NMR (DMSO-d₆, 400 MHz with D₂O): δ 0.88 (t, J=7.2 Hz, 3H), 1.32 (m, 2H), 1.41 (m, 4H), 1.72 (m, 2H), 4.0 (t, J=7.2 Hz, 2H), 6.97 (m, 1H), 7.22 (m, 1H), 7.28 (m, 1H), 7.52 (br s, 1H), 8.03 (br s, 1H). MS ES+ (238.0, 239.0), HPLC (method 7) Rt=11.34 min.

Example 168 Synthesis of 3-(Pyrazol-1-ylmethoxy)-benzamide

3-(Pyrazol-1-ylmethoxy)-benzoic acid methyl ester (250 mg, 1.1 eq.) was taken in a pressure vessel along with 5 ml of aq. ammonia, heated at 110° C. for 12 hr. reaction mass was then poured in water (25 ml), extracted with dichloromethane (25 ml×4). Organic layer was dried over sodium sulphate and concentrated to obtain crude solid. Product was purified by column chromatography using 80% EtOAc-DCM as an eluent over 230-400 mesh silica gel. Pure product was obtained as solid powder (50 mg, 19%). ¹H NMR (DMSO-d₆, 400 MHz with D₂O): δ 6.12 (s, 2H), 6.33 (m, 1H), 7.25 (m, 1H), 7.37 (m, 1H), 7.41 (m, 1H), 7.51 (m, 1H), 7.56 (m, 2H), 7.95 (br s, 1H), 7.99 (m, 1H). MS ES+ (218.0, 235.0-Ammonium adduct), HPLC (method 7) Rt=9.08 min.

Example 169 3-[(2-Methylcyclopropyl)methoxy]benzenecarboxamide

Synthesised according to Method C, scheme 3. Yield 27%, mp 119-121° C., HPLC-MS (method 1): m/z 206 [M+H]⁺, Rt=3.47 min.

Example 170 3-[(5-Methyl-3-pyridinyl)methoxy]benzenecarboxamide

N-Bromosuccinimide (2.13 g, 12 mmol) and subsequently α,α′-azoisobutyronitrile (16 mg, 0.1 mmol) were added to a solution of 3,5-lutidine (1.14 ml, 10 mmol) in CCl₄ (40 ml). The reaction mixture was stirred at reflux for 2 hrs. After cooling, succinimide was removed by filtration and the filtrate was evaporated to smaller volume (10 ml). To this filtrate, a mixture of 3-hydroxybenzenecarboxamide (550 mg, 4 mmol) and K₂CO₃ (830 mg, 6 mmol) in DMF (5 ml) was added and the new reaction mixture was stirred at 60° C. for 24 h. After diluting with CH₂Cl₂ (100 ml), the solution was washed with Na₂CO₃ solution (40 ml) and water (40 ml), dried (Na₂SO₄) and evaporated to dryness, under reduced pressure. The brown oil residue was extracted by trituration with Et₂O (2×10 ml), and from the Et₂O extracts, the precipitant solid was filtered and washed with pentane, to give 70 mg (7.2% yield) of the desired product. Mp 152-154° C., HPLC-MS: m/z 243 [M+H]⁺, Rt=2.28 min.

Example 171 3-[(3-Bromobenzyl)oxy]benzenecarboxamide

Synthesised according to Method B, scheme 2. Yield 54%, mp 129-131° C., HPLC-MS (method 1): m/z 347 [M+H+CH₃CN]⁺, Rt=3.99 min.

3-(Hydroxymethyl)phenyl acetate

To a stirred solution of 3-hydroxybenzylalcohol (1.0 g, 8 mmol, 1 equiv.) in 6.4N KOH solution (1.86 ml, 12 mmol, 1.5 equiv.) at r.t., ice (4 g) was added followed by acetic anhydride (0.95 ml, 10 mmol, 1.25 equiv.). The reaction mixture was stirred at r.t. for 3 h. Water (50 ml) was added and the mixture was stirred for 30 min, before extracting with CH₂Cl₂ (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na₂SO₄) and evaporated to dryness, under reduced pressure. The clear oil residue was purified by column chromatography on silica, eluted with EtOAc/hexane (1:2), to give the desired product as a clear oil (714 mg, 54% yield). HPLC-MS (method 1): m/z 165 [M−H]⁻. Rt=2.52 min.

Example 172 3-[3-(Aminocarbonyl)phenoxy]methylphenyl acetate

Synthesised according to Method C, scheme 3. Yield 32%, HPLC-MS (method 1): m/z 286 [M+H]⁺. Rt=3.44 min.

Example 173 3-[(3-Hydroxybenzyl)oxy]benzenecarboxamide

A solution of K₂CO₃ (500 mg, 3.62 mmol, 5.75 equiv.) in water (5 ml) was added to a solution of 3-[3-(aminocarbonyl)phenoxy]methylphenyl acetate (180 mg, 0.63 mmol, 1 equiv.) and the mixture was stirred at r.t., under N₂, for 3 h; The mixture was acidified with 10% HCl solution to pH 1, and was extracted with EtOAc (2×30 ml). The combined organic extracts were washed with water (30 ml), dried (Na₂SO₄) and evaporated to dryness under reduced pressure, to give a clear oil residue which, after trituration with Et₂O, solidified to a white solid (70 mg, 46% yield). Mp 122-123° C., HPLC-MS (method 1): m/z 244 [M+H]⁺. Rt=2.92 min.

3-Chloro-2-(hexyloxy)isonicotinic acid

A solution of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol, 3 equiv.) in hexanol (10 ml) was stirred at r.t. for 2 h. 2,3-Dichloro-isonicotinic acid (960 mg, 5.0 mmol, 1 equiv.) was added and the reaction mixture was stirred at 100° C. for 16 h. The mixture was diluted with water (100 ml) and pentane (300 ml), and the two phases were separated. The aqueous phase was neutralised with 1N HCl solution to pH 6.0 and extracted with EtOAc (3×80 ml). The combined EtOAc extracts were dried (MgSO₄) and evaporated under reduced pressure to dryness. The residue was triturated with pentane, cooled at 0° C. and the precipitant solid was filtered, to give 410 mg of a white compound (yield 32%). By ¹H-NMR analysis, it consisted of about 80% of the desired product, which was used to the next step without further purification. HPLC-MS: m/z 256 [M−H]⁻, Rt=2.94 min.

Example 174 3-Chloro-2-(hexyloxy)isonicotinamide

Synthesised from 3-chloro-2-(hexyloxy)isonicotinic acid according to Method A. Yield 85% (crude); purified further by preparative TLC, mp 75-77° C., HPLC-MS: m/z 298[M+H+CH₃CN]⁺, Rt=4.16 min.

2-fluoro-3-hydroxybenzenecarboxamide

Synthesised from commercially available 2-fluoro-3-methoxybenzenecarboxamide according to Method H. Yield 82%, mp 196-197° C., HPLC-MS (method 1): m/z 154 [M−H]⁻, Rt=1.24 min.

Example 175-178 (Table F)

Examples 175-178 were synthesised from 2-fluoro-3-hydroxybenzenecarboxamide. Examples 175, 176 and 178 according to Method B, scheme 2 and Example 177 according to Method C, scheme 3.

Example 175 176 Structure

Yield (%) 62 70 mp (° C.) 76-77 91-92 HPLC-MS: 1, 282, [M + H]⁺ 1, 270, [M + H]⁺ method no., m/z, ion Rt (min) 5.13 3.48 Example 177 178 Structure

Yield (%) 7 6 mp (° C.) 98-100 70-72 HPLC-MS: 1, 306, [M + H]⁺ 1, 246, [M + H]⁺ method no., m/z, ion Rt (min) 4.78 3.52

Table of names of product compounds; Examples 175-178:

Example Compound name 175 2-Fluoro-3-(nonyloxy)benzenecarboxamide 176 Butyl 2-[3-(aminocarbonyl)-2-fluorophenoxy]acetate 177 2-Fluoro-3-(10-undecynyloxy)benzenecarboxamide 178 2,6-Difluoro-3-(4-hydroxybutoxy)benzenecarboxamide

Example 179 Methyl 4-[3-(aminocarbonyl)-2,4-difluorophenoxy]-2-butenoate

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 41%, mp 122-123° C., HPLC-MS (method 1): m/z 272 [M+H]⁺, Rt=2.80 min.

4-[3-(aminocarbonyl)-2,4-difluorophenoxy]-2-butenoic acid

A solution of methyl 4-[3-(aminocarbonyl)-2,4-difluorophenoxy]-2-butenoate (1.25 g, 4.61 mmol, 1 equiv.) and NaOH (0.75 g, 18.44 mmol, 4 equiv.) in isopropanol (10 ml) and H₂O (20 ml) was heated under reflux for 1 h. After cooling to r.t., the mixture was acidified with conc. HCl to pH 1. The white precipitant solid was filtered and washed with Et₂O (50 ml), to give 568 mg, 48% yield, mp 187-188° C., HPLC-MS (method 1): m/z 258 [M+H]⁺, Rt=0.98 min. By ¹H-NMR analysis it was determined to be a mixture of isomeres in a ratio (3:2) E:Z.

The aqueous phase was extracted with Et₂O (2×50 ml) and the combined extracts were dried (Na₂SO₄) and evaporated to dryness under reduced pressure, to give a light orange solid, 418 mg, 35% yield, mp 127-128° C., HPLC-MS (method 1): m/z 258 [M+H]⁺, Rt=0.99 min. By ¹H-NMR analysis it was determined to be a mixture of isomeres in a ratio (3:40) E:Z.

Example 180 Butyl 4-[3-(aminocarbonyl)-2,4-difluorophenoxy]-2-butenoate

4-[3-(Aminocarbonyl)-2,4-difluorophenoxy]-2-butenoic acid, mixture of isomeres (3:2) E:Z, (526 mg, 2 mmol, 1 equiv.) was dissolved in dry DMF (5 ml). K₂CO₃ (850 mg, 6 mmol, 3 equiv.) and n-butylbromide (0.23 ml, 2.1 mmol, 1.05 equiv.) were added and the reaction mixture was heated for 70 h at 50° C. and for 1.5 h at r.t. After cooling at r.t., the mixture was diluted with H₂O (50 ml) and extracted with EtOAc (3×40 ml). The combined organic extracts were washed with H₂O (6×30 ml), dried (MgSO₄) and evaporated to dryness under reduced pressure. The oily residue was purified by column chromatography on silica, eluted with CH₂Cl₂ and MeOH/CH₂Cl₂ (1%), to give 364 mg, 57% yield, mp<40° C. HPLC-MS (method 1): m/z 314 [M+H]⁺, Rt=3.88 min. By ¹H-NMR analysis it was determined to be a mixture of isomeres in a ratio (5:7) E:Z. When the same reaction was performed on the acid (3:40) E:Z mixture of isomeres, the product obtained was determined to be a mixture of isomeres in a ratio (1:4) E:Z.

Example 181 Butyl 4-[3-(aminocarbonyl)-2,4-difluorophenoxy]butanoate

4-[3-(Aminocarbonyl)-2,4-difluorophenoxy]-2-butenoic acid (100 mg, 0.32 mmol) was stirred with 5% Rh/C (5 mg) in butanol (5 ml) under H₂, at r.t. for 21 h. The reaction mixture was filtered through a pad of celite and rinsed with CH₂Cl₂ (3×5 ml). The filtrate was evaporated to dryness, under reduced pressure, to give 88 mg of the desired product, yield 87%, mp 53-55° C. HPLC-MS (method 1): m/z 316 [M+H]⁺, Rt=3.49 min.

Example 182-197 (Table G)

Examples 182-197 were synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide: Examples 182, 190, 192, 193 and 195 according to according to Method B, scheme 2 and Examples 183-189, 191, 194 and 196-197 according to Method C, scheme 3.

Example 182 183 184 Structure

Yield (%) 11 4 10 mp (° C.) 130-132 86-88 — HPLC-MS: 1, 269, [M + H]⁺ 1, 254, [M + H]⁺ 1, 254, [M + H]⁺ method no., m/z, ion Rt (min) 2.84 3.15 3.11 Example 185 186 187 Structure

Yield (%) 7 30 9 mp (° C.) 92-93 155-156 111-112 HPLC-MS: 1, 268, [M + H]⁺ 1, 268, [M − H]⁺ 1, 284, [M + H]⁺ method no., m/z, ion Rt (min) 3.49 3.38 3.73 Example 188 189 190 Structure

Yield (%) 17 8.4 13 mp (° C.) 161-162 130-132 194-196 HPLC-MS: 1, 270, [M + H]⁺ 1, 271, [M + H]⁺ 1, 285, [M + H]⁺ method no., m/z, ion Rt (min) 3.42 2.37 2.73 Example 191 192 193 Structure

Yield (%) 8 46 49 mp (° C.) 175-177 172-174 172-173 HPLC-MS: 1, 271, [M + H]⁺ 1, 285, [M + H]⁺ 1, 285, [M + H]⁺ method no., m/z, ion Rt (min) 2.51 2.85 2.80 Example 194 195 Structure

Yield (%) 14 30 mp (° C.) 167-168 103-105 HPLC-MS: 1, 268, [M + H]⁺ 1, 278, [M + H]⁺ method no., m/z, ion Rt (min) 1.86 3.89 Example 196 197 Structure

Yield (%) 3 57 mp (° C.) 137-138 201-202 HPLC-MS: 1,308, [M + H]⁺ 1, 279, [M + H]⁺ method no., m/z, ion Rt (min) 3.51 2.89

Table of names of product compounds; Examples 182-197:

Example Compound name 182 2,6-Difluoro-3-[(5-methyl-3-isoxazolyl)methoxy]benzenecarboxamide 183 2,6-Difluoro-3-(2-furylmethoxy)benzenecarboxamide 184 2,6-Difluoro-3-(3-furylmethoxy)benzenecarboxamide 185 2,6-Difluoro-3-[(5-methyl-2-furyl)methoxy]benzenecarboxamide 186 2,6-Difluoro-3-(2-thienylmethoxy)benzenecarboxamide 187 2,6-Difluoro-3-[(4-methyl-2-thienyl)methoxy]benzenecarboxamide 188 2,6-Difluoro-3-(3-thienylmethoxy)benzenecarboxamide 189 2,6-Difluoro-3-(1,3-thiazol-5-ylmethoxy)benzenecarboxamide 190 2,6-Difluoro-3-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzenecarboxamide 191 2,6-Difluoro-3-(1,3-thiazol-2-ylmethoxy)benzenecarboxamide 192 2,6-Difluoro-3-[(5-methyl-1,3-thiazol-2-yl)methoxy]benzenecarboxamide 193 2,6-Difluoro-3-[(4-methyl-1,3-thiazol-2-yl)methoxy]benzenecarboxamide 194 2,6-Difluoro-3-[(1-methyl-1H-imidazol-2-yl)methoxy]benzenecarboxamide 195 2,6-Difluoro-3-[(3-methylbenzyl)oxy]benzenecarboxamide 196 3-[(3-Ethoxybenzyl)oxy]-2,6-difluorobenzenecarboxamide 197 2,6-Difluoro-3-[(6-methyl-2-pyridinyl)methoxy]benzenecarboxamide

Example 198 2,6-Difluoro-3-[(2-methyl-4-pyridinyl)methoxy]benzenecarboxamide

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method C, scheme 3. The required building block, 4-hydroxymethyl-2-methylpyridine, was synthesised according to the literature method, shown in Scheme 23 (Ragan, J. A., Jones, B. P., Meltz, C. N., Teixeira J. J. Jr.; Synthesis 2002, 483-486. Yield 34%, mp 185-186° C., HPLC-MS (method 1): m/z 279 [M+H]⁺, Rt=2.50 min.

Example 199 2,6-Difluoro-3-([1,3]oxazolo[4,5-b]pyridin-2-ylmethoxy)benzenecarboxamide

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 8%, mp 180-181° C., HPLC-MS (method 1): m/z 306 [M+H]⁺, Rt=2.30 min.

Example 200 2,6-Difluoro-3-(2-quinolinylmethoxy)benzenecarboxamide

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 48%, mp 216-218° C., HPLC-MS (method 1): m/z 315 [M+H]⁺, Rt=3.43 min.

Example 201 3-(1-Benzothiophen-5-ylmethoxy)-2,6-difluorobenzenecarboxamide

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. The required building block, 5-(chloromethyl)-1-benzothiophene, was synthesised by chlorination of commercially available 1-benzothiophen-5-ylmethanol with thionyl chloride. Yield 10%, mp 146-148° C., HPLC-MS (method 1): m/z 320 [M+H]⁺, Rt=3.95 min.

Examples 202-207 (Table H)

Examples 202-207 were synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method C, scheme 3.

Example 202 203 Structure

Yield % 29 9 mp (° C.) 154-156 — HPLC-MS: 1, 320, [M + H]⁺ 1, 304, [M + H]⁺ method no., m/z, ion Rt (min) 3.97 2.52 Example 204 205 Structure

Yield % 13 23 mp (° C.) 84-86 149-150 HPLC-MS: 1, 322, [M + H]⁺ 1, 334, [M + H]⁺ method no., m/z, ion Rt (min) 3.73 3.88 Example 206 207 Structure

Yield % 63 26 mp (° C.) 142-143 135-136 HPLC-MS: 1, 320, [M + H]⁺ 1, 304, [M + H]⁺ method no., m/z, ion Rt (min) 4.02 3.82

Table of names of product compounds; Examples 202-207:

Example Compound name 202 3-(1-Benzothiophen-3-ylmethoxy)-2,6- difluorobenzenecarboxamide 203 2,6-Difluoro-3-(imidazo[1,2-a]pyridin-2- ylmethoxy)benzenecarboxamide 204 3-(2,3-Dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6- difluorobenzenecarboxamide 205 2,6-Difluoro-3-[(5-methyl-1-benzothiophen-2- yl)methoxy]benzenecarboxamide 206 3-(1-Benzothiophen-2-ylmethoxy)-2,6- difluorobenzenecarboxamide 207 3-(1-Benzofuran-2-ylmethoxy)-2,6- difluorobenzenecarboxamide

[5-(Trifluoromethyl)-1-benzothiophen-2-yl]methanol

Pyridine (0.37 ml, 4.72 mmol, 1.5 equiv.) and subsequently cyanuric fluoride (0.53 ml, 6.3 mmol, 2 equiv.) were added to a stirred solution of commercially available 5-(trifluoromethyl)-1-benzothiophene-2-carboxylic acid (776 mg, 3.15 mmol, 1 equiv.) in CH₂Cl₂ (16 ml), kept under N₂, at −20 to −10° C. Precipitation of cyanuric acid occurred and increased gradually as the reaction proceeded. After the mixture was stirred at −20 to −10° C. for 2 h, ice-cold water was added along with 100 ml CH₂Cl₂. Undissolved solids were filtered off; from the filtrate, the organic phase was separated and the aqueous layer was extracted once more with CH₂Cl₂ (50 ml). The combined organic layers were washed with ice-cold water (50 ml), dried (Na₂SO₄) and concentrated under reduced pressure to a small volume (15 ml). NaBH₄ (240 mg, 6.3 mmol, 2 equiv.) was added in one portion, and MeOH (6.5 ml) was then added, dropwise, over 15 min at r.t. The reaction mixture was neutralised with 1N H₂SO₄, and the organic solvents were evaporated under reduced pressure. The residue was taken-up in EtOAc (80 ml) and water (40 ml); the organic layer was separated, and the aqueous layer was extracted with EtOAc (2×60 ml). The combined organic layers were washed with 1N H₂SO₄ and brine, dried (Na₂SO₄) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica, using EtOAc/hexane (10-20% gradient) as eluent, to give 400 mg (54.6% yield) of the required product as a white solid. HPLC-MS (method 1) gave one peak with Rt=4.02 min, but no ionization.

Example 208 2,6-Difluoro-3-[5-(trifluoromethyl)-1-benzothiophen-2-yl]methoxybenzenecarboxamide

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and [5-(trifluoromethyl)-1-benzothiophen-2-yl]methanol according to Method C, scheme 3. Yield 3%, mp 150-152° C., HPLC-MS (method 1): m/z 386 [M−H]⁻, Rt=4.39 min.

Examples 209-217 (Table I)

Examples 209-217 were synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2.

Example 209 210 Structure

Yield (%) 37 62 mp (° C.) 138-139 — HPLC-MS: 1, 305, [M + H]⁺ 1, 339, [M + H]⁺ method no., m/z, ion Rt (min) 3.28 3.72 Example 211 212 Structure

Yield (%) 16 32 mp (° C.) 172-173 150-151 HPLC-MS: 1, 319, [M + H]⁺ 1, 319, [M + H]⁺ method no., m/z, ion Rt (min) 3.60 3.60 Example 213 214 Structure

Yield (%) 50 14 mp (° C.) 160-161 153-155 HPLC-MS: 1, 361, [M + H]⁺ 1, 348, [M − H]⁻ method no., m/z, ion Rt (min) 4.29 3.32 Example 215 216 Structure

Yield (%) 15 25 mp (° C.) 185-186 195-197 HPLC-MS: 1, 321, [M + H]⁺ 1, 339, [M + H]⁺ method no., m/z, ion Rt (min) 3.46 3.67 Example 217 Structure

Yield (%) 60 mp (° C.) 223-224 HPLC-MS: 1, 389, [M + H]⁺ method no., m/z, ion Rt (min) 4.15

Table of names of product compounds; Examples 209-217:

Example Compound name 209 3-(1,3-Benzoxazol-2-ylmethoxy)-2,6-difluorobenzenecarboxamide 210 3-[(5-Chloro-1,3-benzoxazol-2-yl)methoxy]-2,6-difluorobenzenecarboxamide 211 2,6-Difluoro-3-[(6-methyl-1,3-benzoxazol-2-yl)methoxy]benzenecarboxamide 212 2,6-Difluoro-3-[(5-methyl-1,3-benzoxazol-2-yl)methoxy]benzenecarboxamide 213 3-[5-(tert-Butyl)-1,3-benzoxazol-2-yl]methoxy-2,6-difluorobenzenecarboxamide 214 2,6-Difluoro-3-[(5-nitro-1,3-benzoxazol-2-yl)methoxy]benzenecarboxamide 215 3-(1,3-Benzothiazol-2-ylmethoxy)-2,6-difluorobenzenecarboxamide 216 2,6-Difluoro-3-[(5-fluoro-1,3-benzothiazol-2-yl)methoxy]benzenecarboxamide 217 2,6-Difluoro-3-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methoxybenzenecarboxamide

5-Chloro-2-(chloromethyl)-1,3-benzothiazole

4-Chloro-2-amino-benzothiol (4.05 g, 25.4 mmol, 1 equiv.) and 2-chloro-1,1,1-trimethoxy ethane (5.0 ml, 37 mmol, 1.45 equiv.) were heated with stirring at 60° C. for 2 h. The reaction mixture was cooled at r.t. and triturated with diethyl ether (10 ml). The undissolved solid was filtered and rinsed with Et₂O and pentane, to give 1.54 g (28% yield) of the desired product. The mother liquors were evaporated to dryness, the orange solid residue was dissolved in Et₂O (50 ml) and washed consecutively with 1N HCl (25 ml), water (25 ml), 5% NaHCO₃ solution (25 ml) and brine (25 ml). The organic layer was dried (MgSO4) and evaporated to smaller volume, under reduced pressure. The precipitant solid was filtered and washed with Et₂O and pentane, to give a second fraction of the desired product 1.88 g (34% yield). Total yield 62%, mp 102-104° C., HPLC-MS (method 1): m/z 260 [M+H+CH₃CN]⁺, Rt=4.52 min.

Examples 218-221 (Table J)

Examples 218-221 were synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and 5-chloro-2-(chloromethyl)-1,3-benzothiazole according to Method B, scheme 2.

Example 218 219 Structure

Yield (%) 81 67 mp (° C.) 235-236 204-205 HPLC-MS: 1, 355, [M + H]⁺ 1, 337, [M + H]⁺ method no., m/z, ion Rt (min) 3.89 392 Example 220 221 Structure

Yield (%) 50 35 mp (° C.) 240-242 218-220 HPLC-MS: 1, 371, [M + H]⁺ 1, 371, [M + H]⁺ method no., m/z, ion Rt (min) 4.02 3.98

Table of names of product compounds; Examples 218-221:

Example Compound name 218 3-[(5-Chloro-1,3-benzothiazol-2-yl)methoxy]-2,6- difluorobenzenecarboxamide 219 3-[(5-Chloro-1,3-benzothiazol-2-yl)methoxy]-2- fluorobenzenecarboxamide 220 6-Chloro-3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]- 2-fluorobenzenecarboxamide 221 2-Chloro-3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]- 6-fluorobenzenecarboxamide

2-[(5-Chloro-1,3-benzothiazol-2-yl)methoxy]isonicotinonitrile

2-Hydroxy-4-cyano-pyridine (240 mg, 2 mmol, 1 equiv.) was dissolved in DMF (6 ml), K₂CO₃ (415 mg, 3 mmol, 1.5 equiv.) and NaI (60 mg, 0.4 mmol, 0.2 equiv.) were added and the mixture was stirred at r.t. for 10 min. 5-Chloro-2-(chloromethyl)-1,3-benzothiazole (436 mg, 2 mmol, 1 equiv.) was added and the reaction mixture was stirred at 60° C. for 3 h and at r.t. overnight. By addition of H₂O, brown solid precipitated, which was filtered, rinsed with H₂O, dried and re-crystallised from CH₃CN. Yield 280 mg (46%), mp 224-227° C., HPLC-MS (method 1): m/z 302 [M+H]⁺, Rt=3.80 min. By ¹³C-NMR analysis it was identified to be the N-alkylated derivative (Scheme 24). The DMF-H₂O mother liquors were evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica, eluted with EtOAc/hexane (10%-100% gradient) to give 45 mg (7.5% yield) of a brown solid, HPLC-MS (method 1): m/z 302 [M+H]⁺, Rt=4.86 min. By ¹³C-NMR analysis, it was identified to be the desired O-alkylated derivative (Scheme 24).

Example 222 2-[(5-Chloro-1,3-benzothiazol-2-yl)methoxy]isonicotinamide

2-[(5-Chloro-1,3-benzothiazol-2-yl)methoxy]isonicotinonitrile (40 mg, 0.13 mmol) was dissolved in conc. H₂SO₄ (0.36 ml) and the solution was heated at 40° C., under vigorous stirring. Water (50 mg) was added dropwise and the mixture was stirred at 40° C. for 3 h. After cooling at −5° C., crushed ice (25 ml) was added quickly, with vigorous stirring, and the mixture was stirred at r.t. for two more hours. Ammonia solution was added (pH 10) and the precipitant solid was filtered, rinsed with H₂O and dried. The brown solid was purified by preparative TLC, eluted with EtOAc, to give 20 mg (47% yield), mp 220-222° C., HPLC-MS (method 1): m/z 320 [M+H]⁺, Rt=3.76 min.

2-(Chloromethyl)-4-ethyl-1,3-benzothiazole

(Method J) A solution of 4-ethyl-1,3-benzothiazol-2-amine (1.0 g, 5.6 mmol, 1 equiv.) and KOH (7.4 g, 112.2 mmol, 20 equiv.) in 2-methoxy-ethanol (9 ml) and H₂O (9 ml), was stirred under N₂ and under reflux, for 20 h. After cooling at r.t., the mixture was poured into water (150 ml) and extracted with CH₂Cl₂ (2×40 ml). The aqueous phase was neutralised with conc. HCl and extracted again with CH₂Cl₂ (3×70 ml). The combined neutral extracts were washed with water (2×60 ml), dried (Na₂SO₄) and evaporated to dryness under reduced pressure. The yellow-green semi-solid residue (790 mg) was mixed with 2-chloro-1,1,1-trimethoxy ethane (1.62 g, 10.4 mmol) and the mixture was stirred, under N₂, at 60° C., for 4 h. Volatiles were removed by evaporation under reduced pressure and the brown liquid residue was purified by column chromatography on silica, eluted with CH₂Cl₂/hexane (10% and 50%), to give a yellow liquid (406 mg, 34% yield over two steps). HPLC-MS (method 1): m/z 212 [M+H]⁺, Rt=5.00 min

Example 223 3-[(4-Ethyl-1,3-benzothiazol-2-yl)methoxy]-2,6-difluorobenzenecarboxamide

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and 2-(chloromethyl)-4-ethyl-1,3-benzothiazole according to Method B, scheme 2. Yield 17%, mp 184-186° C., HPLC-MS (method 1): m/z 349 [M+H]⁺, Rt=4.16 min.

2-(Chloromethyl)-6-methoxy-1,3-benzothiazole

Synthesised from commercially available 6-methoxy-1,3-benzothiazol-2-amine according to Method J, scheme 25. It was used crude on the next step.

Example 224 2,6-Difluoro-3-[(6-methoxy-1,3-benzothiazol-2-yl)methoxy]benzenecarboxamide

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and 2-(chloromethyl)-6-methoxy-1,3-benzothiazole according to Method B, scheme 2. Yield 19%, mp 190-192° C., HPLC-MS (method 1): m/z 351 [M+H]⁺, Rt=3.50 min.

Example 225 3-(Cyanomethoxy)-2,6-difluorobenzenecarboxamide

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 86%, mp 122-123° C., HPLC-MS (method 1): m/z 213 [M+H]⁺, Rt=1.97 min.

Example 226 3-[(4-Chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluorobenzenecarboxamide

(Method K) A solution of KOH (15.15 g, 270 mmol, 20 equiv.) in H₂O (25 ml) was added to a solution of 4-chloro-1,3-benzothiazol-2-amine (2.5 g, 13.5 mmol, 1 equiv.) in 2-methoxy-ethanol (25 ml) and the reaction mixture was heated under reflux overnight. After cooling at r.t., the mixture was diluted with H₂O (200 ml), acidified with 5N HCl solution to pH 4 and extracted with CH₂Cl₂ (3×150 ml). The combined organic extracts were washed with brine (100 ml), dried (Na₂SO₄) and concentrated under reduced pressure to dryness, to give 1.5 g (70% yield). From this crude residue, 167 mg (assuming 1.05 mmol), were mixed with 3-(cyanomethoxy)-2,6-difluorobenzenecarboxamide (150 mg, 0.7 mmol) and the mixture was stirred at 120° C., in a pre-heated oil bath, under N₂, for 2 h. EtOH (2 ml) was added and the reaction mixture was heated for a further 2 h. After cooling at r.t., the solid was filtered, washed with EtOH and re-crystallised from EtOAc/pentane, to give the desired product as a pale yellow solid, 62 mg (25% yield on second step). HPLC-MS (method 1): m/z 355 [M+H]⁺, Rt=3.75 min.

Example 227 3-[(6-Chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluorobenzenecarboxamide

Synthesised from 6-chloro-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzene carboxamide, according to Method K, scheme 26. Yield 38% (second step), mp 190-191° C., HPLC-MS (method 1): m/z 355 [M+H]⁺, Rt=3.85 min.

Example 228 2,6-Difluoro-3-[(4-methyl-1,3-benzothiazol-2-yl)methoxy]benzenecarboxamide

Synthesised from 4-methyl-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzene carboxamide, according to Method K, scheme 26. Yield 36% (second step), mp 201-202° C., HPLC-MS (method 1): m/z 335 [M+H]⁺, Rt=3.79 min.

Example 229 2,6-Difluoro-3-[(6-methyl-1,3-benzothiazol-2-yl)methoxy]benzenecarboxamide

Synthesised from 6-methyl-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzene carboxamide, according to Method K, scheme 26. Yield 17% (second step), HPLC-MS (method 1): m/z 335 [M+H]⁺, Rt=3.70 min.

Example 230 2,6-Difluoro-3-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]methoxybenzenecarboxamide

Synthesised from 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzenecarboxamide, according to Method K, scheme 26. Yield 34% (second step), mp 174-175° C., HPLC-MS (method 1): m/z 405 [M+H]⁺, Rt=4.14 min.

6-Propyl-1,3-benzothiazol-2-amine

A solution of Br₂ (3.8 ml, 74 mmol, 2 equiv.) in glacial AcOH (18.5 ml) was added dropwise, at <25° C., to a stirred solution of 4-propylamine (5.0 g, 37 mmol, 1 equiv.) and ammonium thiocyanate (5.63 g, 74 mmol, 2 equiv.) in glacial AcOH (110 ml). The resulting mixture was stirred at r.t. for 2 h, diluted with H₂O (700 ml) and extracted with EtOAc (2×250 ml). The aqueous layer was alkalised with aqueous ammonia solution to pH 10 and extracted with EtOAc (3×300 ml). The combined alkaline extracts were washed with H₂O (2×200 ml), dried and evaporated to dryness under reduced pressure, to give the desired product as a white solid, 2.34 g (33% yield), mp 120-122° C. HPLC-MS (method 1): m/z 193 [M+H]⁺, Rt=3.92 min.

Example 231 2,6-Difluoro-3-[(6-propyl-1,3-benzothiazol-2-yl)methoxy]benzenecarboxamide

Synthesised from 6-propyl-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzenecarboxamide, according to Method K, scheme 26. Yield 18% (second step), mp 173-175° C. HPLC-MS (method 1): m/z 363 [M+H]⁺, Rt=4.35 min.

5-Bromo-2-(bromomethyl)-1,3-benzothiazole

N-Bromosuccinimide (4.45 g, 25 mmol, 1.4 equiv.) and subsequently α,α′azoisobutyronitrile (110 mg, 0.7 mmol, 0.04 equiv.) were added to a solution of 5-bromo-2-methyl-benzothiazole (4.07 g, 17.85 mmol, 1 equiv.) in CCl₄ (110 ml). The reaction mixture was stirred at reflux for 24 hrs. After cooling, succinimide was removed by filtration and was rinsed with CCl₄ (100 ml). The filtrate was evaporated to dryness under reduced pressure and the orange solid residue was purified by column chromatography on silica, eluted with CH₂Cl₂/hexane (20%-70% gradient), to give the desired product as a white solid, 2.15 g (39% yield). Mp 116-117, HPLC-MS (method 1): m/z 308 [M+H]⁺, Rt=4.84 min. The reaction gave also 1.40 g (20% yield) of the by-product 5-bromo-2-dibromomethyl-benzothiazole, as well as 0.89 g (22%) of un-reacted starting material.

3-[(5-Bromo-1,3-benzothiazol-2-yl)methoxy]-2,6-difluorobenzenecarboxamide

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and 5-bromo-2-(bromomethyl)-1,3-benzothiazole, according to Method B, scheme 2. Yield 81%, mp 244-246° C., HPLC-MS (method 1): m/z 399, 401 [M+H]⁺, Rt=3.98 min.

Example 232 2,6-Difluoro-3-[5-(4-pyridinyl)-1,3-benzothiazol-2-yl]methoxybenzenecarboxamide

A mixture of 3-[(5-bromo-1,3-benzothiazol-2-yl)methoxy]-2,6-difluorobenzenecarboxamide (168 mg, 0.42 mmol, 1 equiv.), 4-pyridine boronic acid (98 mg, 0.63 mmol, 1.5 equiv.) and 2M aqueous Na₂CO₃ solution (0.42 ml, 0.82 mmol, 2 equiv.) were suspended in dioxane (3.5 ml) and the mixture was degassed and flushed with N₂. Tetrakis(triphenylphosphine)palladium(0) catalyst (37 mg, 0.031 mmol, 0.075 equiv.) was added and the reaction mixture was heated under reflux for 12 h. After cooling at r.t., the mixture was diluted with H₂O and the precipitant solid was filtered and rinsed with H₂O, IMS, IMS/Et₂O and Et₂O. Re-crystallised from CH₃CN, to give the desired product as an off-white solid, 47 mg (28% yield), mp 255-258° C. HPLC-MS: m/z 398 [M+H]⁺, Rt=3.28 min.

Examples 233-241 (Table K)

Examples 233-241 were synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2.

Example 233 234 Structure

Yield (%) 58 25 mp (° C.) 207-209 198-199 HPLC-MS: 1, 347, [M + H]⁺ 1, 382, [M + H]⁺ method no., m/z, ion Rt (min) 3.96 3.89 Example 235 236 Structure

Yield (%) 63 54 mp (° C.) 208-210 222-224 HPLC-MS: 1, 347, [M + H]⁺ 1, 361, [M + H]⁺ method no., m/z, ion Rt (min) 3.84 4.13 Example 237 238 Structure

Yield (%) 6 (only ~75% pure) 17 mp (° C.) — 188-189 HPLC-MS: 1, 362, [M + H]⁺ 1, 332, [M + H]⁺ method no., m/z, ion Rt (min) 3.75 3.17 Example 239 240 Structure

Yield (%) 60 44 mp (° C.) 177-178 164-165 HPLC-MS: 1, 332, [M + H]⁺ 1, 332, [M + H]⁺ method no., m/z, ion Rt (min) 3.62 3.65 Example 241 Structure

Yield (%) 77 mp (° C.) 172-173 HPLC-MS: 1, 362, [M + H]⁺ method no., m/z, ion Rt (min) 3.76

Table of names of product compounds; Examples 233-241:

Example Compound name 233 2,6-Difluoro-3-[(2-phenyl-1,3-thiazol-4-yl)methoxy]benzenecarboxamide 234 3-[5-(4-Chlorophenyl)-1,3,4-thiadiazol-2-yl]methoxy-2,6-difluorobenzenecarboxamide 235 2,6-Difluoro-3-[(4-phenyl-1,3-thiazol-2-yl)methoxy]benzenecarboxamide 236 2,6-Difluoro-3-[2-(4-methylphenyl)-1,3-thiazol-4-yl]methoxybenzenecarboxamide 237 3-[(2-Anilino-1,3-thiazol-4-yl)methoxy]-2,6-difluorobenzenecarboxamide 238 2,6-Difluoro-3-[(5-phenyl-1,3,4-oxadiazol-2-yl)methoxy]benzenecarboxamide 239 2,6-Difluoro-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methoxy]benzenecarboxamide 240 2,6-Difluoro-3-[(3-phenyl-1,2,4-oxadiazol-5-yl)methoxy]benzenecarboxamide 241 2,6-Difluoro-3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5- yl]methoxybenzenecarboxamide

Example 242 2,6-Difluoro-3-[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]methoxybenzenecarboxamide

(Method L) Boron tribromide solution (1.0 M in CH₂Cl₂, 1.5 ml, 1.5 mmol, 2 equiv.) was added slowly, dropwise to stirred suspension of 2,6-difluoro-3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]methoxybenzenecarboxamide (272 mg, 0.75 mmol, 1 equiv.) in CH₂Cl₂ (5 ml), at r.t., under N₂. The reaction mixture was stirred at r.t. for 4 h and poured into water (20 ml). CH₂Cl₂ (10 ml) was added and the biphasic mixture was stirred for 30 min. at r.t. The white un-dissolved solid was filtered, washed with water and Et₂O, to give 170 mg (65% yield), mp 209-210° C., HPLC-MS (method 1): m/z 348 [M+H]⁺, Rt=3.00 min.

Examples 243-250 (Table L)

Examples 243-250 were Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2.

Example 243 244 245 Structure

No example

Yield (%) 38 81 mp (° C.) 168-169 173-174 HPLC-MS: 1, 398, [M− H]⁻ 1, 350, [M + H]⁺ method no., m/z, ion Rt (min) 4.27 3.81 Example 246 247 Structure

Yield (%) 80 82 mp (° C.) 166-168 169-170 HPLC-MS: 1, 407, [M + H + CH₃CN]⁺ 1, 346, [M + H]⁺ method no., m/z, ion Rt (min) 4.10 3.98 Example 248 249 Structure

Yield (%) 80 53 mp (° C.) 134-135 132-133 HPLC-MS: 1, 374, [M + H]⁺ 1, 388, [M + H]⁺ method no., m/z, ion Rt (min) 4.47 4.62 Example 250 Structure

Yield (%) 33 mp (° C.) 141-142 HPLC-MS: 1, 360, [M + H]⁺ method no., m/z, ion Rt (min) 4.24

Table of names of product compounds: Examples 243-250:

Example Compound name 243 2,6-Difluoro-3-(3-[4-(trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-ylmethoxy)benzenecarboxamide 245 2,6-Difluoro-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5- yl]methoxybenzenecarboxamide 246 3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methoxy-2,6- difluorobenzenecarboxamide 247 2,6-Difluoro-3-[3-(4-methylphenyl)-1,2,4-oxadiazol-5- yl]methoxybenzenecarboxamide 248 2,6-Difluoro-3-[3-(4-isopropylphenyl)-1,2,4-oxadiazol-5- yl]methoxybenzenecarboxamide 249 3-(3-[4-(tert-Butyl)phenyl]-1,2,4-oxadiazol-5-ylmethoxy)-2,6- difluorobenzenecarboxamide 250 3-[3-(4-Ethylphenyl)-1,2,4-oxadiazol-5-yl]methoxy-2,6- difluorobenzenecarboxamide

tert-Butyl N-4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]phenylcarbamate

To a solution of 4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]aniline (950 mg, 4.53 mmol, 1 equiv.), Et₃N (0.20 ml, 5.44 mmol, 1.2 equiv.) and dimethylaminopyridine (catalytic), Boc anhydride (1.04 g, 4.75 mmol, 1.05 equiv.) was added portionwise, and the reaction mixture was stirred at r.t. for 3 days. The solvent was evaporated under reduced pressure, the residue was triturated with Et₂O and the solid was removed by filtration. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica, eluted with EtOAc/hexane (20%), to give a cream solid, 780 mg (55% yield). About 70% pure by HPLC-MS (method 1): m/z 308 [M−H]⁻, Rt=4.72 min. It was used without further purification on the next step.

tert-Butyl N-[4-(5-[3-(aminocarbonyl)-2,4-difluorophenoxy]methyl-1,2,4-oxadiazol-3-yl)phenyl]carbamate

Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and tert-butyl N-4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]phenylcarbamate, according to Method B, scheme 2, at r.t. Yield 42%, mp 165-166° C., HPLC-MS (method 1): m/z 447 [M+H]⁺, Rt=4.10 min.

Example 251 3-[3-(4-Aminophenyl)-1,2,4-oxadiazol-5-yl]methoxy-2,6-difluorobenzenecarboxamide hydrochloride salt

tert-Butyl N-[4-(5-[3-(aminocarbonyl)-2,4-difluorophenoxy]methyl-1,2,4-oxadiazol-3-yl)phenyl]carbamate (300 mg, 0.67 mmol, 1 equiv.) was dissolved in 4N HCl in dioxane (7 ml, 28 mmol, 42 equiv.) and the reaction mixture was stirred at r.t. overnight. Volatiles were removed under reduced pressure, the residue was triturated with dry Et₂O and the solid formed was filtered and rinsed with dry Et₂O. The crude product (200 mg) was taken-up in EtOH (2 ml) and was triturated with 2N HCl in Et₂O solution (0.3 ml) and dry Et₂O. The white solid was filtered and washed with dry Et₂O, to give 110 mg of the desired product (43% yield). HPLC-MS (method 1): m/z 347 [M+H−HCl]⁺, Rt=2.98 min.

Examples 252-266 (Table M)

Examples 252, 254-256 and 258-266 were synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. Examples 253 and 257 were synthesised from 2,6-difluoro-3-[3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]methoxybenzene carboxamide according to Method L.

Example 252 252a Structure

Yield (%) 60 73 mp (° C.) 148-149 263-264 HPLC-MS: 1, 346, [M + H]⁺ 1, 362, [M + H]⁺ method no., m/z, ion Rt (min) 3.95 3.45 Example 253 254 Structure

Yield (%) 54 56 mp (° C.) 164-165 173-174 HPLC-MS: 1, 348, [M + H]⁺ 1, 366, [M + H]⁺ method no., m/z, ion Rt (min) 3.52 3.82 Example 255 256 Structure

Yield (%) 71 96 mp (° C.) 146-148 149-151 HPLC-MS: 1, 367, [M + H]⁺ 1, 362, [M + H]⁺ method no., m/z, ion Rt (min) 4.10 3.75 Example 257 258 Structure

Yield (%) 37 76 mp (° C.) 197-199 155-157 HPLC-MS: 1, 348, [M + H]⁺ 1, 400, [M + H]⁺ method no., m/z, ion Rt (min) 3.11 4.23 Example 259 260 Structure

Yield (%) 62 64 mp (° C.) 179-180 155-157 HPLC-MS: 1, 377, [M + H]⁺ 1, 400, [M + H]⁺ method no., m/z, ion Rt (min) 3.78 3.92 Example 261 262 Structure

Yield (%) 24 36 mp (° C.) 192-194 195-197 HPLC-MS: 1, 392, [M + H]⁺ 1, 333, [M + H]⁺ method no., m/z, ion Rt (min) 3.43 2.70 Example 263 264 Structure

Yield (%) 79 30 mp (° C.) 137-139 128-130 HPLC-MS: 1, 376, [M + H]⁺ 1, 430, 432, [M + H]⁺ method no., m/z, ion Rt (min) 3.88 4.0  Example 265 266 Structure

Yield (%) 83 47 mp (° C.) 123-125 88-89 HPLC-MS: 1, 380, [M + H]⁺ 1, 346, [M + H]⁺ method no., m/z, ion Rt (min) 3.92 3.58

Table of names of product compounds; Examples 252-266:

Example Compound name 252 2,6-Difluoro-3-[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]methoxybenzenecarboxamide 252a 2,6-Difluoro-3-[3-(2-methoxyphenyl)-1,2,4-oxadiazol-5- yl]methoxybenzenecarboxamide 253 2,6-Difluoro-3-[3-(2-hydroxyphenyl)-1,2,4-oxadiazol-5- yl]methoxybenzenecarboxamide 254 3-[3-(2-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methoxy-2,6-difluorobenzenecarboxamide 255 3-[3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methoxy-2,6-difluorobenzenecarboxamide 256 2,6-Difluoro-3-[3-(3-methoxyphenyl)-1,2,4-oxadiazol-5- yl]methoxybenzenecarboxamide 257 2,6-Difluoro-3-[3-(3-hydroxyphenyl)-1,2,4-oxadiazol-5- yl]methoxybenzenecarboxamide 258 2,6-Difluoro-3-(3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5- ylmethoxy)benzenecarboxamide 259 2,6-Difluoro-3-[3-(3-nitrophenyl)-1,2,4-oxadiazol-5-yl]methoxybenzenecarboxamide 260 3-[3-(2,6-Dichlorophenyl)-1,2,4-oxadiazol-5-yl]methoxy-2,6- difluorobenzenecarboxamide 261 3-[3-(2,4-Dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]methoxy-2,6- difluorobenzenecarboxamide 262 2,6-Difluoro-3-[3-(3-pyridinyl)-1,2,4-oxadiazol-5-yl]methoxybenzenecarboxamide 263 2,6-Difluoro-3-(3-[(4-methylphenoxy)methyl]-1,2,4-oxadiazol-5- ylmethoxy)benzenecarboxamide 264 3-(3-[(2,6-Dichlorophenoxy)methyl]-1,2,4-oxadiazol-5-ylmethoxy)-2,6- difluorobenzenecarboxamide 265 3-[3-(4-Chlorobenzyl)-1,2,4-oxadiazol-5-yl]methoxy-2,6-difluorobenzenecarboxamide 266 3-[(3-Benzyl-1,2,4-oxadiazol-5-yl)methoxy]-2,6-difluorobenzenecarboxamide

4-Chloro-N-hydroxy-benzamide

To a solution of 4-chlorobenzonitrile (10.0 g, 73.0 mmol) in EtOH (250 mL) was added hydroxylamine hydrochloride (5.03 g, 73.0 mmol) and NaOH (2.90 g, 73.0 mmol). The resulting reaction mixture was refluxed for 15 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated in vacuo and used as such for the next step (crude yield 12.0 g, 66%).

5-Bromomethyl-3-(4-chloro-phenyl)-[1,2,4]oxadiazole

Bromoacetyl bromide (1.50 mL, 17.58 mmol) was added to 4-Chloro-N-hydroxy-benzamide (1.0 g, 5.86 mmol) and K₂CO₃ (3.18 g, 23.44 mmol). The reaction mixture was heated at 100° C. for 15 min. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 1% EtOAc-Hexane) to get the desired product (0.44 g, 28%) as a white solid.

Examples 267-270 (Table N)

The compounds of Examples 267-270 were synthesised according to the following general procedure: To a solution of 5-bromomethyl-3-(4-chloro-phenyl)[1,2,4]oxadiazole (A) in 2 ml of anhydrous DMF was added reactant (B) and potassium carbonate (C). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using ethyl acetate/hexane (45:55) as the eluent to provide the product compound.

TABLE N Example 267 Product 3-[3-(4-Chloro-phenyl)-[1,2,4]oxadiazol-5- ylmethoxy]-2-fluoro-benzamide Reaction scheme

Reactant 2-Fluoro-3-hydroxy-benzamide (B) Quantities 0.03 g, 0.10 mmol; 0.017 g, 0.10 mmol; of A; B; C 0.053 g, 0.35 mmol Yield 0.019 g, 50%, off white solid ¹H-NMR δ 5.72 (s, 2H), 7.17-7.25 (m, 2H), 7.39- (DMSO- 7.43 (m, 1H), 7.80 (m, 3 H), 7.80 (br s, d₆, 400 1H) and 8.03 (d, J = 8.80 Hz, 2H) MHz) MS-ES+ 348.07 HPLC 8, 16.33 method no., Rt (min) Example 268 Product 5-[3-(4-Chloro-phenyl)-[1,2,4]oxadiazol- 5-ylmethoxy]-2-fluoro-benzamide Reaction scheme

Reactant 2-Fluoro-5-hydroxy-benzamide (B) Quantities 0.07 g, 0.25 mmol; 0.04 g, 0.25 mmol; of A; B; C 0.124 g, 0.90 mmol Yield 0.025 g, 27%, white solid ¹H-NMR δ 5.63 (s, 2H), 7.23-7.33 (m, 3H), 7.65- (DMSO- 7.73 (m, 4H) and 8.03 (d, J = 8.40 Hz, d₆, 400 2H) MHz) MS-ES+ 348.11 HPLC 8, 16.56 method no., Rt (min) Example 269 Product 6-Chloro-3-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol- 5-ylmethoxy]-2-fluoro-benzamide Reaction scheme

Reactant 6-Chloro-2-fluoro-3-hydroxy-benzamide (B) Quantities 0.07 g, 0.25 mmol; 0.048 g, 0.25 mmol; 0.124 g, of A; B; C 0.90 mmol Yield 0.070 g, 71%, white solid ¹H-NMR δ 5.74 (s, 2H), 7.30-7.39 (m, 2H), 7.67 (d, J = 8.40 (DMSO- Hz, 2H), 7.88 (br s, 1H), 8.03 (d, J = 8.40 Hz, 2H) d₆, 400 and 8.16 (br s, 1H) MHz) MS-ES+ 382.03 HPLC 8, 16.53 method no., Rt (min) Example 270 Product 2-Chloro-3-[3-(4-chloro-phenyl)- [1,2,4]oxadiazol-5-ylmethoxy]-6-fluoro- benzamide Reaction scheme

Reactant 2-Chloro-6-fluoro-3-hydroxy-benzamide (B) Quantities 0.070 g, 0.25 mmol; 0.048 g, 0.25 mmol; of A; B; C 0.124 g, 0.9 mmol Yield 0.013 g, 13%, white solid ¹H-NMR δ 5.73 (s, 2H), 7.27-7.37 (m, 2H), 7.65 (d, J = (DMSO- 8.40 Hz, 2H), 7.87 (br s, 1H), 8.03 (d, J = 8.40 d₆, 400 Hz, 2H) and 8.14 (br s, 1H) MHz) MS-ES+ 382.03 HPLC 8, 16.48 method no., Rt (min)

2-Benzyloxymethyl-4-(4-chloro-phenyl)-thiazole

To the solution of 2-Benzyloxy-thioacetamide (3.0 g, 16.57 mmol) in 3 ml of DMF was added 2-Bromo-1-(4-chloro-phenyl)-ethanone (3.0 g, 12.87 mmol). The reaction mixture was heated at 130° C. for 24 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 2% EtOAc-Hexane) to get the desired product (2.0 g, 49%). The corresponding cyano derivative was also prepared by the same general method.

[4-(4-Chloro-phenyl)-thiazol-2-yl]-methanol

A solution of 2-Benzyloxymethyl-4-(4-chloro-phenyl)-thiazole (2.0 g, 6.34 mmol) in 25 ml of DCM was cooled to −78° C. followed by addition of BBr₃ (2.38 ml, 25.3 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO₃ (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 40% EtOAc-Hexane) to get the desired product (0.8 g, 57%). The corresponding cyano derivative was also prepared by the same general method.

2-Bromomethyl-4-(4-chloro-phenyl)-thiazole

To the solution of [4-(4-Chloro-phenyl)-thiazol-2-yl]-methanol (0.80 g, 3.55 mmol) in 10 ml of toluene was added PBr₃ (0.51 ml, 5.33 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.17 g, 17%). The corresponding cyano derivative was also prepared by the same general method.

Examples 271-276 (Table O)

The compounds of Examples 271-276 were synthesised according to the following general procedure: To a solution of reactant (A) in anhydrous DMF was added reactant (B) and potassium carbonate (C). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane as the eluent to provide the product compound.

TABLE O Example 271 Product 3-[4-(4-Chloro-phenyl)-thiazol-2- ylmethoxy]-2-fluoro-benzamide Reaction scheme

Reactant (A) 2-bromomethyl-4-(4-chloro-phenyl)- thiazole Reactant (B) 2-Fluoro-3-hydroxy-benzamide Quantities A; B; 0.070 g, 0.24 mmol; 0.037 g, 0.24 C; volume DMF mmol; 0.116 g, 0.8 mmol; 2 ml Ratio ethyl 30:70 acetate:hexane Yield 0.035 g, 40%, white solid ¹H NMR δ 5.60 (s, 2H), 7.20 (m, 2H), 7.44 (m, (DMSO-d₆, 400 1H), 7.53 (d, J = 8.40 Hz, 2H), 7.66 (br MHz) s, 1H), 7.79 (br s, 1H), 8.0 (d, J = 8.40 Hz, 2H) and 8.25 (s, 1H) MS-ES+ 363.22 HPLC method 9, 16.91 no., Rt (min) Example 272 Product 5-[4-(4-Chloro-phenyl)-thiazol-2- ylmethoxy]-2-fluoro-benzamide Reaction scheme

Reactant (A) 2-bromomethyl-4-(4-chloro-phenyl)- thiazole Reactant (B) 2-fluoro-5-hydroxy-benzamide Quantities A; B; 0.07 g, 0.24 mmol; 0.037 g, 0.24 C; volume DMF mmol; 0.116 g, 0.84 mmol; 2 ml Ratio ethyl 30:70 acetate:hexane Yield 0.020 g, 23%, white solid ¹H NMR δ 5.52 (s, 2H), 7.24 (m, 2H), 7.33 (m, (DMSO-d₆, 400 1H), 7.53 (d, J = 8.40 Hz, 2H), 7.72 MHz) (m, 2H), 8.01 (d, J = 8.40 Hz, 2H) and 8.25 (s, 1H) MS-ES+ 363.04 HPLC method 9, 17.06 no., Rt (min) Example 273 Product 6-Chloro-3-[4-(4-chloro-phenyl)-thiazol-2- ylmethoxy]-2-fluoro-benzamide Reaction scheme

Reactant (A) 2-bromomethyl-4-(4-chloro-phenyl)-thiazole Reactant (B) 6-chloro-2-fluoro-3-hydroxy-benzamide Quantities A; B; 0.070 g, 0.24 mmol; 0.045 g, 0.24 mmol; 0.116 g, C; volume DMF 0.8 mmol; 2 ml Ratio ethyl 30:70 acetate:hexane Yield 0.017 g, 17%, white solid ¹H NMR δ 5.62 (s, 2H), 7.29-7.32 (m, 1H), 7.37-7.41 (m, (DMSO-d₆, 400 1H), 7.53 d, J = 8.80 Hz, 2H), 7.86 (br s, 1H), 8.0 MHz) (d, J = 8.80 Hz, 2H), 8.14 (br s, 1H) and 8.26 (s, 1H) MS-ES+ 396.99 HPLC method 8, 17.00 no., Rt (min) Example 274 Product 2-Chloro-3-[4-(4-chloro-phenyl)-thiazol-2- ylmethoxy]-6-fluoro-benzamide Reaction scheme

Reactant (A) 2-bromomethyl-4-(4-chloro-phenyl)-thiazole Reactant (B) 2-chloro-6-fluoro-3-hydroxy-benzamide Quantities A; B; 0.07 g, 0.24 mmol; 0.045 g, 0.24 mmol; 0.116 C; volume DMF g, 0.84 mmol; 2 ml Ratio ethyl 30:70 acetate:hexane Yield 0.042 g, 43%, white solid ¹H NMR δ 5.60 (s, 2H), 7.30 (m, 1H), 7.38 (m, 1H), (DMSO-d₆, 400 7.53 (d, J = 8.40 Hz, 2H), 7.86 (br s, 1H), 8.0 MHz) (d, J = 8.40 Hz, 2H), 8.13 (br s, 1H) and 8.24 (s, 1H) MS-ES+ 397.20 HPLC method 8, 16.98 no., Rt (min) Example 275 Product 2-[4-(4-Chloro-phenyl)-thiazol-2-ylmethoxy]- isonicotinamide Reaction scheme

Reactant (A) 2-bromomethyl-4-(4-chloro-phenyl)-thiazole Reactant (B) 2-hydroxy-isonicotinamide Quantities A; B; 0.10 g, 0.34 mmol; 0.048 g, 0.34 mmol; 0.167 g, C; volume DMF 0.12 mmol; 2 ml Ratio ethyl 30:70 acetate:hexane Yield 0.027 g, 12%, white solid ¹H NMR δ 5.46 (s, 2H), 6.63 (m, 1H), 6.90 (s, 1H), 7.51 (d, (DMSO-d₆, 400 J = 8.40 Hz, 2H), 7.70 (br s, 1H), 7.98 (m, 3H) MHz) and 8.15 (m, 2H) MS-ES+ 346.12 HPLC method 8, 14.96 no., Rt (min) Example 276 Product 3-[4-(4-Cyano-phenyl)-thiazol-2-ylmethoxy]- 2,6-difluoro-benzamide Reaction scheme

Reactant (A) 4-(2-Bromomethyl-thiazol-4-yl)-benzonitrile Reactant (B) 2,6-Difluoro-3-hydroxy-benzamide Quantities A; B; 0.55 g, 1.9 mmol; 0.34 g, 1.90 mmol; 0.95 g, C; volume DMF 6.92 mmol; 8 ml Ratio ethyl 50:50 acetate:hexane Yield 0.41 g, 56%, white solid ¹H NMR δ 5.60 (s, 2H), 7.12 (t, J = 8.80 Hz, 1H), 7.40 (DMSO-d₆, 400 (m, 1H), 7.89 (br s, 1H), 7.94 (d, J = 8.40 Hz, MHz) 2H), 8.17 (m, 3H) and 8.48 (s, 1H) MS-ES+ 372.07 HPLC method 8, 15.52 no., Rt (min)

4-(4-Methoxy-phenyl)-2-methyl-thiazole

The mixture of thioacetamide (16.0 g, 213 mmol) and 2-bromo-1-(4-methoxy-phenyl)-ethanone (4.0 g, 17.5 mmol) was heated at 140° C. for 24 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3×100 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 1% EtOAc-Hexane) to get the desired product (2.5 g, 69%).

5-Bromo-2-bromomethyl-4-(4-methoxy-phenyl)-thiazole

To the solution 4-(4-Methoxy-phenyl)-2-methyl-thiazole (5.0, 24.3 mmol) in CCl₄ (20 mL) was added NBS (7.43 g, 41.74 mmol) and the reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 1% ethyl acetate/hexane to give the desired product (3.0 g, 34%).

3-[5-Bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide

To a solution of 5-Bromo-2-bromomethyl-4-(4-methoxy-phenyl)-thiazole (0.50 g, 1.37 mmol) in 5 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.23 g, 1.37 mmol) and potassium carbonate (0.75 g, 5.43 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (30:70) as the eluent to provide the title compound (0.30 g, 48%).

Examples 277-287 (Table P)

The compounds of Examples 277-287 were synthesised according to the following general procedure: To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (A) in 5 ml of anhydrous DMF and water (2.5 ml) was added reactant (B) and potassium phosphate (C). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(triphenyl phosphine) palladium (II) (D). The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (45% EtOAc-Hexane) to get the desired product compound.

TABLE P Example 277 Product 2,6-Difluoro-3-[5-(2-hydroxy-phenyl)-4- (4-methoxy-phenyl)-thiazol-2- ylmethoxy]-benzamide Reaction scheme

Reactant (B) 2-hydroxyphenyl boronic acid Quantities A; 0.20 g, 0.44 mmol; 0.12 g, 0.88 mmol; B; C; D 0.11 g, 0.53 mmol; 0.046 g, 0.068 mmol Silica gel 60-120M Yield 0.005 g, 3%, white solid ¹H NMR δ 3.72 (s, 3H), 5.54 (s, 2H), 6.80 (m, (DMSO-d₆, 3H), 6.85 (m, 1H), 7.08-7.23 (m, 3H), 400 MHz) 7.39-7.46 (m, 3H), 7.88 (br s, 1H), 8.17 (br s, 1H) and 9.90 (br s, 1H) MS-ES+ 469.31 HPLC method 8, 16.04 no., Rt (min) Example 278 Product 2,6-Difluoro-3-[5-(3-hydroxy-phenyl)-4- (4-methoxy-phenyl)-thiazol-2- ylmethoxy]-benzamide Reaction scheme

Reactant (B) 3-hydroxyphenyl boronic acid Quantities A; 0.20 g, 0.44 mmol; 0.12 g, 0.88 mmol; B; C; D 0.11 g, 0.53 mmol; 0.046 g, 0.068 mmol Silica gel 60-120M Yield 0.02 g, 10%, white solid ¹H NMR δ 3.75 (s, 3H), 5.54 (s, 2H), 6.77 (m, (DMSO-d₆, 3H), 6.91 (m, 2H), 7.16 (m, 2H), 7.45 400 MHz) (m, 3H), 7.89 (br s, 1H), 8.17 (br s, 1H) and 9.64 (br s, 1H) MS-ES+ 469.30 HPLC method 8, 15.70 no., Rt (min) Example 279 Product 2,6-Difluoro-3-[5-(4-hydroxy-phenyl)-4-(4- methoxy-phenyl)-thiazol-2-ylmethoxy]-benzamide Reaction scheme

Reactant (B) 4-hydroxyphenyl boronic acid Quantities A; 0.20 g, 0.44 mmol; 0.12 g, 0.88 mmol; 0.11 g, B; C; D 0.53 mmol; 0.046 g, 0.068 mmol Silica gel 60-120M Yield 0.02 g, 10%, white solid ¹H NMR δ 3.74 (s, 3H), 5.52 (s, 2H), 6.78 (d, J = 8.40 Hz, (DMSO-d₆, 2H), 6.89 (d, J = 8.40 Hz, 2H), 7.13 (m, 3H), 7.37- 400 MHz) 7.45 (m, 3H), 7.89 (br s, 1H), 8.17 (br s, 1H) and 9.79 (br s, 1H) MS-ES+ 469.29 HPLC method 8, 15.60 no., Rt (min) Example 280 Product 2,6-Difluoro-3-[5-(2-methoxy-phenyl)-4-(4- methoxy-phenyl)-thiazol-2-ylmethoxy]- benzamide Reaction scheme

Reactant (B) 2-methoxyphenyl boronic acid Quantities A; 0.10 g, 0.20 mmol; 0.06 g, 0.41 mmol; 0.05 g, B; C; D 0.24 mmol; 0.021 g, 0.03 mmol Silica gel 60-120M Yield 0.019 g, 18%, white solid ¹H NMR δ 3.70 (s, 3H), 3.72 (s, 3H), 5.54 (s, 2H), 6.85 (DMSO-d₆, (d, J = 8.80 Hz, 2H), 6.95 (m, 1H), 7.14-7.19 400 MHz) (m, 3H), 7.36 (d, J = 8.80 Hz, 2H), 7.44 (m, 2H), 7.87 (br s, 1H) and 8.16 (br s, 1H) MS-ES+ 483.40 HPLC method 9, 16.85 no., Rt (min) Example 281 Product 2,6-Difluoro-3-[5-(3-methoxy-phenyl)-4-(4- methoxy-phenyl)-thiazol-2-ylmethoxy]-benzamide Reaction scheme

Reactant (B) 3-methoxyphenyl boronic acid Quantities A; 0.10 g, 0.20 mmol; 0.06 g, 0.41 mmol; 0.05 g, B; C; D 0.24 mmol; 0.021 g, 0.03 mmol Silica gel 60-120M Yield 0.025 g, 24%, white solid ¹H NMR δ 3.69 (s, 3H), 3.75 (s, 3H), 5.55 (s, 2H), 6.89- (DMSO-d₆, 6.96 (m, 5H), 7.14 (m, 1H), 7.31 (m, 1H), 7.38- 400 MHz) 7.46 (m, 3H), 7.89 (br s, 1H) and 8.17 (br s, 1H) MS-ES+ 483.42 HPLC method 9, 16.97 no., Rt (min) Example 282 Product 2,6-Difluoro-3-[5-(4-methoxy-phenyl)-4-(4- methoxy-phenyl)-thiazol-2-ylmethoxy]- benzamide Reaction scheme

Reactant (B) 4-methoxyphenyl boronic acid Quantities A; 0.10 g, 0.20 mmol; 0.06 g, 0.41 mmol; 0.05 g, B; C; D 0.24 mmol; 0.021 g, 0.03 mmol Silica gel 60-120M Yield 0.018 g, 17%, yellow solid ¹H NMR δ 3.74 (s, 3H), 3.77 (s, 3H), 5.53 (s, 2H), 6.90 (DMSO-d₆, (d, J = 8.40 Hz, 2H), 6.97 (d, J = 8.40 Hz, 2H), 400 MHz) 7.13 (m, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.44 (m, 1H), 7.89 (br s, 1H) and 8.16 (br s, 1H) MS-ES+ 483.23 HPLC method 8, 17.03 no., Rt (min) Example 283 Product 2,6-Difluoro-3-[5-(2-amino-phenyl)-4-(4-methoxy- phenyl)-thiazol-2-ylmethoxy]-benzamide Reaction scheme

Reactant (B) 2-aminophenyl boronic acid Quantities A; 0.10 g, 0.20 mmol; 0.09 g, 0.54 mmol; 0.10 g, B; C; D 0.48 mmol; 0.021 g, 0.03 mmol Silica gel 60-120M Yield 0.042 g, 41%, light yellow solid ¹H NMR δ 3.72 (s, 3H), 4.94 (br s, 2H), 5.54 (s, 2H), 6.57 (DMSO-d₆, (t, J = 7.20 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.84 400 MHz) (m, 2H), 7.0 (m, 1H), 7.14 (m, 2H), 7.51 (m, 3H), 7.89 (br s, 1H) and 8.18 (br s, 1H) MS-ES+ 468.02 HPLC method 9, 16.70 no., Rt (min) Example 284 Product 2,6-Difluoro-3-[5-(3-amino-phenyl)-4-(4- methoxy-phenyl)-thiazol-2-ylmethoxy]- benzamide Reaction scheme

Reactant (B) 3-aminophenyl boronic acid Quantities A; 0.10 g, 0.20 mmol; 0.07 g, 0.54 mmol; 0.102 B; C; D g, 0.48 mmol; 0.021 g, 0.03 mmol Silica gel 60-120M Yield 0.015 g, 14%, light yellow solid ¹H NMR δ 3.74 (s, 3H), 5.25 (br s, 2H), 5.53 (s, 2H), (DMSO-d₆, 6.44 (m, 1H), 6.56 (m, 2H), 6.89 (m, 2H), 7.03 400 MHz) (m, 1H), 7.13 (m, 1H), 7.42 (m, 3H), 7.88 (br s, 1H) and 8.17 (br s, 1H) MS-ES+ 468.03 HPLC method 9, 16.04 no., Rt (min) Example 285 Product 2,6-Difluoro-3-[5-(4-amino-phenyl)-4-(4-methoxy- phenyl)-thiazol-2-ylmethoxy]-benzamide Reaction scheme

Reactant (B) 4-aminophenyl boronic acid Quantities A; 0.10 g, 0.20 mmol; 0.07 g, 0.54 mmol; 0.102 g, B; C; D 0.48 mmol; 0.021 g, 0.03 mmol Silica gel 60-120M Yield 0.01 g, 9%, brown solid ¹H NMR δ 3.74 (s, 3H), 5.42 (br s, 2H), 5.50 (s, 2H), 6.54 (DMSO-d₆, (m, 2H), 6.89 (d, J = 8.80 Hz, 2H), 6.99 (d, J = 400 MHz) 8.40 Hz, 2H), 7.13 (m, 1H), 7.40 (m, 3H), 7.89 (br s, 1H) and 8.17 (br s, 1H) MS-ES+ 468.31 HPLC method 8, 16.06 no., Rt (min) Example 286 Product 3-[5-Cyclopropyl-4-(4-methoxy-phenyl)- thiazol-2-ylmethoxy]-2,6-difluoro-benzamide Reaction scheme

Reactant (B) cyclopropyl boronic acid Quantities A; 0.10 g, 0.20 mmol; 0.37 g, 0.43 mmol; 0.05 g, B; C; D 0.26 mmol; 0.021 g, 0.03 mmol Silica gel 230-400M Yield 0.01 g, 10%, white solid ¹H NMR δ 0.66 (m, 2H), 1.11 (m, 2H), 2.20 (m, 1H), (DMSO-d₆, 3.80 (s, 3H), 5.44 (s, 2H), 7.02 (m, 2H), 7.11 400 MHz) (m, 1H), 7.39 (m, 1H), 7.80 (m, 2H), 7.88 (br s, 1H) and 8.16 (br s, 1H) MS-ES+ 417.11 HPLC method 9, 17.12 no., Rt (min) Example 287 Product 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-5-phenyl-thiazol-2-ylmethoxy]- benzamide Reaction scheme

Reactant (B) phenyl boronic acid Quantities A; 0.10 g, 0.20 mmol; 0.05 g, 0.43 mmol; 0.05 g, 0.26 mmol; 0.021 g, B; C; D 0.03 mmol Silica gel 230-400M Yield 0.02 g, 22% ¹H NMR δ 3.75 (s, 3H), 5.56 (s, 2H), 6.90 (d, J = 8.80 Hz, 2H), 7.14 (t, J = 8.80 (DMSO-d₆, Hz, 1H), 7.36-7.45 (m, 8H), 400 MHz) 7.89 (br s, 1H) and 8.17 (br s, 1H) MS-ES+ 453.23 HPLC method 9, 13.35 no., Rt (min)

Example 288 2,6-Difluoro-3-[4′-(4-methoxy-phenyl)-[4,5′]bithiazolyl-2′-ylmethoxy]-benzamide

To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.20 g, 0.043 mmol) in 5 ml of anhydrous DMF was added 4-tributylstannyl thiazole (0.16 g, 0.43 mmol) and degassed the reaction mixture for 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.05 g, 0.043 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to room temperature added water (25 mL) and extracted the compound with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/Hexane (40:60) as the eluent to provide the title compound as white solid (0.072 g, 36%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.80 (s, 3H), 5.56 (s, 2H), 7.01 (d, J=8.80 Hz, 2H), 7.13 (m, 1H), 7.41-7.50 (m, 4H), 7.90 (br s, 1H), 8.18 (br s, 1H) and 9.18 (s, 1H). MS ES+ (460.32), HPLC (method II) Rt=16.37 min.

Example 289 3-[5-Cyano-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide

To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.20 g, 0.43 mmol) in pyridine (4.0 mL) was added CuCN (0.19 g, 2.19 mmol). The reaction mixture was heated to 150° C. in microwave for 2 h. After the completion of the reaction, pH was adjusted to 3-4 with 1N HCl solution and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 45% EtOAc-Hexane) to get the desired product (0.02 g, 11%) as a brown solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 3.79 (s, 3H), 5.67 (s, 2H), 7.16 (m, 3H), 7.42 (m, 1H), 7.88 (br s, 1H), 8.03 (d, J=8.80 Hz, 2H) and 8.19 (br s, 1H). MS ES+ (402.07), HPLC (method I) Rt=16.60 min.

2,6-Difluoro-3-[4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-benzamide

To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (2.0 g, 4.37 mmol) in the 50 ml of acetic acid was added Zn dust (2.0 g). The reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and pH was adjusted to 8-9 with NaOH solution and extracted with ethyl acetate (3×150 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.8 g, 50%) as a white solid.

Example 290 2,6-Difluoro-3-[4-(4-hydroxy-phenyl)-thiazol-2-ylmethoxy]-benzamide

A solution of 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-benzamide (0.20 g, 0.53 mmol) in 15 ml of DCM was cooled to −78° C. followed by addition of BBr₃ (0.2 ml, 2.14 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO₃ (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated, the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as light yellow solid (0.06 g, 31%). ¹H NMR (DMSO-d₆, 400 MHz): δ 5.55 (s, 2H), 6.83 (d, J=8.40 Hz, 2H), 7.13 (m, 1H), 7.40 (m, 1H), 7.78 (d, J=8.80 Hz, 2H), 7.88 (br s, 1H), 7.91 (s, 1H), 8.17 (br s, 1H) and 9.64 (br s, 1H). MS ES+ (363.25), HPLC (method I) Rt=14.57 min.

4-(2-Methyl-thiazol-4-yl)-benzonitrile

The compound was prepared following the general method as described in the preparation of 4-(4-Methoxy-phenyl)-2-methyl-thiazole (Scheme 31).

4-(5-Bromo-2-bromomethyl-thiazol-4-yl)-benzonitrile

The compound was prepared following the general method as described in the preparation of 5-Bromo-2-bromomethyl-4-(4-methoxy-phenyl)-thiazole (Scheme 31).

Example 291 3-[5-Bromo-4-(4-cyano-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide

To a solution of 4-(5-Bromo-2-bromomethyl-thiazol-4-yl)-benzonitrile (0.43 g, 1.20 mmol) in 5 ml of anhydrous DMF was added 2,6-difluoro-3-hydroxy-benzamide (0.20 g, 1.20 mmol) and potassium carbonate (0.58 g, 4.20 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (30:70) as the eluent to provide the title compound as a white solid (0.35 g, 66%). ¹H NMR (DMSO-d₆, 400 MHz): δ 5.57 (s, 2H), 7.13 (m, 1H), 7.44 (m, 1H), 7.89 (br s, 1H), 8.0 (d, J=8.40 Hz, 2H), 8.10 (d, J=8.40 Hz, 2H) and 8.17 (br s, 1H). MS ES+ (450.09), HPLC (method I) Rt=16.127 min.

Trifluoromethoxy phenyl-N-hydroxy-benzamide

To a solution of 4-Trifluoromethoxybenzonitrile (1.0 g, 5.0 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (0.365 g, 5.0 mmol) and NaOH (0.212 g, 5.0 mmol). The resulting reaction mixture was refluxed for 15 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated in vacuo and used as such for the next step (crude yield 12.0 g, 66%).

5-Bromomethyl-3-(Tri Fluoro Methoxy phenyl)-[1,2,4]oxadiazole

Bromoacetyl bromide (2.0 mL, 23.12 mmol) was added to trifluoromethoxy-N-hydroxy-benzamide (0.40 g, 5.86 mmol) and K₂CO₃ (0.87 g, 6.0 mmol). The reaction mixture was heated at 100° C. for 15 min. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 3% EtOAc-Hexane) to get the desired product (0.25 g, 43%) as a white solid.

Example 292 3-[3-(4-Trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-5-ylmethoxy]-2-fluoro-benzamide

To a solution of 5-Bromomethyl-3-(Trifluoromethoxy phenyl)-[1,2,4]oxadiazole (0.24 g, 1.0 mmol) in 2.5 ml of anhydrous DMF was added 2,6-difluoro-3-hydroxy benzamide (0.18 g, 1.0 mmol) and potassium carbonate (0.516 g, 3.7 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.090 g, 20%). ¹H NMR (DMSO-d₆, 400 MHz): δ 5.71 (s, 2H), 7.15 (t, J=7.60 Hz, 1H), 7.40 (m, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.91 (br s, 1H), 8.15 (d, J=8.40 Hz, 2H) and 8.18 (br s, 1H). MS ES+ (416.28), HPLC (method I) Rt=16.79 min.

4-Chloromethyl-2-(4-methoxy-phenyl)-oxazole (General method)

To a solution of 1,3 dichloroacetone (0.504 g, 3.90 mmol) in toluene (5 ml) was added 4-methoxy benzamide (0.30 g, 1.90 mmol). The reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 15% EtOAc-Hexane) to get the desired product (0.37 g, 83%).

Example 293 2,6-Difluoro-3-[2-(4-methoxy-phenyl)-oxazol-4-ylmethoxy]-benzamide

To a solution of 4-Chloromethyl-2-(4-methoxy-phenyl)-oxazole (0.100 g, 0.4 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.077 g, 0.40 mmol) and potassium carbonate (0.216 g, 1.50 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.044 g, 27%). ¹H NMR (DMSO-d₆, 400 MHz): δ 4.01 (s, 3H), 5.12 (s, 2H), 7.10 (m, 3H), 7.40 (m, 1H), 7.85 (br s, 1H), 7.93 (d, J=8.80 Hz, 2H), 8.13 (br s, 1H) and 8.25 (s, 1H). MS ES+ (361.16), HPLC (method I) Rt=15.47 min.

Example 294 3-[2-(4-Chloro-phenyl)-oxazol-4-ylmethoxy]-2,6-difluoro-benzamide

To a solution of 4-Chloromethyl-2-(4-chloro-phenyl)-oxazole (0.20 g, 0.87 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.15 g, 0.78 mmol) and potassium carbonate (0.363 g, 2.60 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.10 g, 31%). ¹H NMR (DMSO-d₆, 400 MHz): δ 5.14 9s, 2H), 7.12 (t, J=9.20 Hz, 1H), 7.40 (m, 1H), 7.63 (d, J=8.40, 2H), 7.85 (br s, 1H), 8.0 (d, J=8.40 Hz, 2H), 8.13 (br s, 1H) and 8.36 (s, 1H). MS ES+ (365.13), HPLC (method I) Rt=16.36 min.

Example 295 2,6-Difluoro-3-(2-p-tolyl-oxazol-4-ylmethoxy)-benzamide

To a solution of 4-Chloromethyl-2-p-tolyl-oxazole (0.10 g, 0.50 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.08 g, 0.50 mmol) and potassium carbonate (0.233 g, 1.50 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.03 g, 18%). ¹H NMR (DMSO-d₆, 400 MHz): δ 2.37 (s, 3H), 5.13 (s, 2H), 7.11 (m, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.41 (m, 1H), 7.88 (m, 3H), 8.12 (br s, 1H) and 8.29 (s, 1H). MS ES+ (345.24), HPLC (method I) Rt=16.07 min.

2-(4-Methoxy-phenyl)-4,5-dimethyl-oxazole (General method)

A mixture of 3-Chloro-2-butanone (2.1 g, 10.0 mmol) and 4-methoxybenzamide (0.30 g, 1.0 mmol) was heated at 115° C. for 15 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 20% EtOAc-Hexane) to get the desired product (0.17 g, 42%) as a white solid. The corresponding chloro derivative was also prepared by the same general method.

4-Bromomethyl-2-(4-methoxy-phenyl)-5-methyl-oxazole

To the solution of 4-Bromomethyl-2-(4-methoxy-phenyl)-5-methyl-oxazole (0.17 g, 0.80 mmol) in acetonitrile (4.0 mL) was added NBS (7.43 g, 41.74 mmol). The reaction mixture was stirred at 25° C. for 1 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was cooled to 0° C. and 2 ml of water was added. The resulting precipitate was filtered and dried to give the desired product (0.11 g, 46%). The corresponding chloro derivative was also prepared by the same general method.

Example 296 2,6-Difluoro-3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzamide

To a solution of 4-Bromomethyl-2-(4-methoxy-phenyl)-5-methyl-oxazole (0.10 g, 0.35 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.061 g, 0.35 mmol) and potassium carbonate (0.171 g, 1.05 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.117 g, 87%). ¹H NMR (DMSO-d₆, 400 MHz): δ 2.42 (s, 3H), 3.82 (s, 3H), 5.06 (s, 2H), 7.10 (m, 3H), 7.37 (m, 1H), 7.86 (m, 3H) and 8.13 (br s, 1H). MS ES+ (375.12), HPLC (method I) Rt=15.78 min.

Example 297 3-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-difluoro-benzamide

To a solution of 4-Bromomethyl-2-(4-chloro-phenyl)-5-methyl-oxazole (0.12 g, 0.42 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.072 g, 0.42 mmol) and potassium carbonate (0.203 g, 1.20 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.01 g, 6%). ¹H NMR (DMSO-d₆, 400 MHz): δ 2.49 (s, 3H), 5.09 (s, 2H), 7.11 (m, 1H), 7.38 (m, 1H), 7.60 (d, J=8.40 Hz, 2H), 7.85 (br s, 1H), 7.95 (d, J=8.40 Hz, 2H) and 8.13 (br s, 1H). MS ES+ (379.25), HPLC (method I) Rt=16.71 min

2,5-Dibromo-3-nitro-pyridine

To a solution of 5-Bromo-3-nitro-pyridin-2-ol (10.0 g, 45.66 mmol) in 70 ml of toluene and 7 ml of DMF was added PBr₃ (6.60 ml, 68.49 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3×200 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (10.30 g, 80.03%).

2,5-Dibromo-pyridin-3-ylamine

To the solution of 2,5-Dibromo-3-nitro-pyridine (10.30 g, 35.47 mmol) in the 100 ml of ethanol was added SnCl₂ (24.0 g, 106.42 mmol) slowly. The reaction mixture was heated at 80° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (250 mL) was added, white solid separated out, then, basified the reaction mixture with NaOH Solution. To this added the 250 ml of ethyl acetate. Filtered it and washed the residue with ethyl acetate, layers are separated, dried (Na₂SO₄), filtered, concentrated to give the desired product (6.20 g, 67.39%).

2-Benzyloxy-N-(2,5-dibromo-pyridin-3-yl)-acetamide

To the solution of 2,5-Dibromo-pyridin-3-ylamine (8.6 g, 34.12 mmol) in 50 ml of DCM was added triethylamine (5.3 ml, 37.53 mmol). Cooled the reaction mixture to 0° C. To this added the solution of 2-benzyloxy acetyl chloride (7.45 g, 40.95 mmol) in 35 ml of DCM. The reaction mixture was stirred at 25° C. for 12 hr. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (10:90) as the eluent to provide the title compound (3.2 g, 24.17%).

2-Benzyloxymethyl-5-bromo-thiazolo[5,4-b]pyridine

To the solution of 2-Benzyloxy-N-(2,5-dibromo-pyridin-3-yl)-acetamide (2.5 g, 6.248 mmol) in 30 ml of toluene was added Lawesson's reagent (1.51 g, 3.74 mmol). The reaction mixture was heated at 120° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.60 g, 76.5%).

5-bromo-2-bromomethyl-thiazolo[5,4-b]pyridine

A solution of 2-Benzyloxymethyl-5-bromo-thiazolo[5,4-b]pyridine (1.60 g, 4.77 mmol) DCM (15 mL) was cooled to −78° C. followed by addition of BBr₃ (2.27 ml, 23.86 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO₃ (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (2.0 g, Crude yield).

Example 298 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide

To a solution of 5-bromo-2-bromomethyl-thiazolo[5,4-b]pyridine (2.0 g, 6.493 mmol) in 10 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (1.01 g, 5.84 mmol) and potassium carbonate (3.09 g, 22.72 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound (1.80 g, 69%). ¹H NMR (DMSO-d₆, 400 MHz): δ 5.72 (s, 2H), 7.12 (t, J=7.60 Hz, 1H), 7.39 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H) and 8.80 (m, 2H). MS ES+ (402.08), HPLC (method I) Rt=15.50 min.

3-(5-Allyl-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide

To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.15 g, 0.37 mmol) in 5 ml of anhydrous DMF was added allyl tributyltin (0.26 ml, 0.86 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.007 g, 0.0056 mmol) was then added and the reaction mixture was heated at 120° C. for 1 h under the nitrogen atmosphere. Then reaction mixture was cooled to room temperature added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (100-200 M) using ethyl acetate/Hexane (60:40) as the eluent to provide the title compound (0.10 g, 75%).

Example 299 2,6-Difluoro-3-(5-propyl-thiazolo[5,4-b]pyridin-2-ylmethoxy)-benzamide

To a solution of 3-(5-Allyl-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.018 g, 0.049 mmol) in 5 ml of anhydrous methanol was added Pd—C (10%, 5 mg) and the reaction mixture was stirred at 25° C. for 12 h under hydrogen atmosphere. The reaction mixture was filtered over the bed of celite and the filtrate was evaporated to dryness under reduced pressure to give the title compound as white solid (0.0078 g, 43%). ¹H NMR (DMSO-d₆, 400 MHz); δ 0.91 (m, 3H), 1.65 (m, 2H), 2.74 (m, 2H), 5.69 (s, 2H), 7.12 (m, 1H), 7.39 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H), 8.27 (br s, 1H) and 8.52 (br s, 1H). MS ES+ (364.11), HPLC (method I) Rt=15.85 min.

Example 300 2,6-Difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-thiazolo[5,4-b]pyridin-2-ylmethoxy]-benzamide

To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.10 g, 0.24 mmol) in 5 ml of anhydrous DMF was added 1-methyl-2-tributylstannanyl-1H-imidazole (0.120 g, 0.32 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.004 g, 0.0037 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. The reaction mixture was then cooled to room temperature, added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/hexane (40:60) as the eluent to provide the title compound as brick red solid (0.020 g, 20%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.14 (s, 3H), 5.67 (s, 2H), 7.07 (m, 1H), 7.28-7.37 (m, 2H), 7.87 (m, 2H), 8.28 (s, 1H), 8.53 (s, 1H) and 8.75 (br s, 1H). MS ES+ (402.22), HPLC (method I) Rt=12.05 min.

Example 301 2,6-Difluoro-3-[5-(1-methyl-1H-pyrrol-2-yl)-thiazolo[5,4-b]pyridin-2-ylmethoxy]-benzamide

To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.10 g, 0.24 mmol) in 5 ml of anhydrous DMF was added 1-methyl-2-tributylstannanyl-1H-pyrrole (0.120 g, 0.32 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.004 g, 0.0037 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. The reaction mixture was then cooled to room temperature, added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/Hexane (40:60) as the eluent to provide the title compound as yellow solid (0.032 g, 32%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.73 (s, 3H), 5.72 (s, 2H), 6.13 (br s, 1H), 6.40 (br s, 1H), 6.97 (s, 1H), 7.12 (m, 1H), 7.42 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H), 8.48 (s, 1H) and 8.75 (s, 1H). MS ES+ (401.26), HPLC (method I) Rt=15.61 min.

Example 302 2,6-Difluoro-3-(5-phenyl-thiazolo[5,4-b]pyridin-2-ylmethoxy)-benzamide

To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.20 g, 0.49 mmol) in 4 ml of DMF and water (2.0 ml) was added phenyl boronic acid (0.12 g, 0.99 mmol) and potassium phosphate (0.13 g, 0.59 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(tri phenyl phosphine) palladium (II) (0.070 g, 0.099 mmol). The reaction mixture was heated at 120° C. for 2 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (100-200 M, 60% EtOAc-Hexane) to get the desired product (0.080 g, 41%) as a beige solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 5.74 (s, 2H), 7.10 (m, 1H), 7.41-7.56 (m, 4H), 7.85 (m, 3H), 8.19 (m, 1H), 8.71 (br s, 1H) and 8.98 (br s, 1H). MS ES+ (398.09), HPLC (method I) Rt=16.07 min.

4-Chloromethyl-2-n-tolyl-thiazole (Representative example)

To a solution of 1,3 dichloroacetone (0.84 g, 6.62 mmol) in toluene (5 ml) was added 4-methylthiobenzamide (0.50 g, 3.31 mmol) and the reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 15% EtOAc-Hexane) to get the desired product (0.49 g, 67%). The other derivatives were also prepared by the same general method.

3-(4-Chloromethyl-thiazol-2-yl)-phenol

To a solution of 1,3 dichloroacetone (0.42 g, 3.26 mmol) in toluene (5 mL) was added 3-hydroxythiobenzamide (0.25 g, 1.63 mmol) and the reaction mixture was heated at 120° C. for 1 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness, added water and extracted with EtOAc (×3). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (0.14 g, 38%).

2-Benzyloxymethyl-4-(4-chloro-phenyl)-oxazole (Representative Procedure)

To a solution of 2-Benzyloxy-acetamide (1.40 g, 8.56 mmol) in 4 ml of DMF was added 2-Bromo-1-(4-chloro-phenyl)-ethanone (2.0 g, 8.56 mmol) and the reaction mixture was heated at 130° C. for 6 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (1.1 g, 44%).

2-Bromomethyl-4-(4-chloro-phenyl)-oxazole (Representative procedure)

A solution of 2-Benzyloxymethyl-4-(4-chloro-phenyl)-oxazole (1.10 g, 3.6 mmol) in 10 ml of DCM was cooled to −78° C. followed by addition of BBr₃ (1.76 ml, 18.0 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO₃ (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.5 g, 49%, crude).

Examples 303-310 (Table Q)

The compounds of Examples 303-310 were synthesised according to the following general procedure: To a solution of reactant (A) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (B) and potassium carbonate (C). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the product compound.

TABLE Q Example 303 304 Product 2,6-Difluoro-3-(2-p-tolyl-thiazol-4- 2,6-Difluoro-3-[2-(4-hydroxy- ylmethoxy)-benzamide phenyl)-thiazol-4-ylmethoxy]- benzamide Reaction scheme

Reactant (A) 4-Chloromethyl-2-p-tolyl-thiazole 4-(4-Chloromethyl-thiazol-2-yl)- phenol Quantities A; B; 0.100 g, 0.4 mmol; 0.069 g, 0.40 mmol; 0.25 g, 1.10 mmol; 0.17 g, 0.99 C 0.18 g, 1.30 mmol mmol; 0.535 g, 3.87 mmol Yield 0.022 g, 13%, white solid 0.012 g, 3%, white solid ¹H NMR δ 2.36 (s, 3H), 5.28 (s, 2H), 7.09 (t, J = δ 5.25 (s, 2H), 6.85 (m, 2H), 7.09 (DMSO-d₆, 400 8.40 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), (m, 1H), 7.40 (m, 1H), 7.66 (s, 1H), MHz) 7.40 (m, 1H), 7.75 (s, 1H), 7.84 (m, 3H) 7.78 (m, 2H), 7.85 (br s, 1H), 8.13 and 8.13 (br s, 1H) (br s, 1H) and 10.03 (br s, 1H) MS-ES+ 361.14 363.14 HPLC method 8, 16.63 8, 14.53 no., Rt (min) Example 305 306 Product 2,6-Difluoro-3-[2-(4-fluoro-phenyl)-thiazol-4- 3-[2-(4-Chloro-phenyl)-thiazol-4-ylmethoxy]- ylmethoxy]-benzamide 2,6-difluoro-benzamide Reaction scheme

Reactant (A) 4-Chloromethyl-2-(4-fluoro-phenyl)-thiazole 4-Chloromethyl-2-(4-chloro-phenyl)-thiazole Quantities A; B; 0.15 g, 0.65 mmol; 0.10 g, 0.59 mmol; 0.27 g, 0.06 g, 0.27 mmol; 0.04 g, 0.27 mmol; 0.12 g, C 1.97 mmol 0.93 mmol Yield 0.06 g, 25%, white solid 0.035 g, 34%, white solid ¹H NMR δ 5.29 (s, 2H), 7.11 (t, J = 8.80 Hz, 1H), 7.33-7.43 δ 5.30 (s, 2H), 7.11 (m, 1H), 7.40 (m, 1H), (DMSO-d₆, 400 (m, 3H), 7.81 (s, 1H), 7.85 (br s, 1H), 8.0 (m, 2H) 7.59 (d, J = 8.80 Hz, 2H), 7.86 (m, 2H), 7.97 MHz) and 8.13 (br s, 1H) (d, J = 8.80 Hz, 2H) and 8.14 (br s, 1H) MS-ES+ 365.03 381.16 HPLC method 8, 16.18 8, 16.88 no., Rt (min) Example 307 308 Product 2,6-Difluoro-3-[2-(4-trifluoromethoxy-phenyl)- 2,6-Difluoro-3-[2-(3-hydroxy-phenyl)-thiazol-4- thiazol-4-ylmethoxy]-benzamide ylmethoxy]-benzamide Reaction scheme

Reactant (A) 4-Chloromethyl-2-(4-trifluoromethoxy-phenyl)- 3-(4-Chloromethyl-thiazol-2-yl)-phenol thiazole Quantities A; B; 0.04 g, 0.11 mmol; 0.02 g, 0.11 mmol; 0.056 g, 0.12 g, 0.53 mmol; 0.08 g, 0.49 mmol; 0.26 g, C 0.38 mmol 1.93 mmol Yield 0.008 g, 16%, white solid 0.014 g, 7%, white solid ¹H NMR δ 5.31 (s, 2H), 7.12 (t, J = 8.80 Hz, 1H), 7.40 (m, δ 5.29 (s, 2H), 6.89 (m, 1H), 7.09 (m, 1H), (DMSO-d₆, 400 1H), 7.52 (d, J = 8.40 Hz, 2H), 7.87 (br s, 2H), 7.28-7.41 (m, 4H), 7.78 (s, 1H), 7.86 (br s, MHz) 8.09 (d, J = 8.40 Hz, 2H) and 8.15 (br s, 1H) 1H), 8.13 (br s, 1H) and 9.79 (s, 1H) MS-ES+ 431.21 363.12 HPLC method 8, 17.13 8, 14.66 no., Rt (min) Example 309 310 Product 3-[4-(4-Chloro-phenyl)-oxazol-2-ylmethoxy]-2,6- 2,6-Difluoro-3-(4-phenyl-oxazol-2-ylmethoxy)- difluoro-benzamide benzamide Reaction scheme

Reactant (A) 2-Bromomethyl-4-(4-chloro-phenyl)-oxazole 2-Bromomethyl-4-phenyl-oxazole Quantities A; B; 0.07 g, 0.24 mmol; 0.037 g, 0.24 mmol; 0.11 g, 0.2 g, 0.84 mmol; 0.14 g, 0.84 mmol; 0.405 g, C 0.84 mmol 2.94 mmol Yield 0.02 g, 22%, white solid 0.04 g, 14%, light yellow solid ¹H NMR δ 5.38 (s, 2H), 7.12 (m, 1H), 7.40 (m, 1H), 7.52 δ 5.39 (s, 2H), 7.13 (t, J = 8.80 Hz, 1H), 7.32- (DMSO-d₆, 400 (d, J = 8.40 Hz, 2H), 7.80 (d, J = 8.40 Hz, 2H), 7.46 (m, 4H), 7.78 (d, J = 7.20 Hz, 2H), 7.88 MHz) 7.88 (br s, 1H), 8.16 (br s, 1H) and 8.73 (s, 1H) (br s, 1H), 8.16 (br s, 1H) and 8.70 (s, 1H) MS-ES+ 365.03 331.15 HPLC method 9, 16.25 8, 15.46 no., Rt (min)

4-(4-Methoxy-phenyl)-2-methyl-oxazole

Prepared as per the method mentioned in Scheme 31.

5-Bromo-2-bromomethyl-4-(4-methoxy-phenyl)-oxazole

Prepared as per the method mentioned in Scheme 31.

3-[5-Bromo-4-(4-methoxy-phenyl)-oxazol-2-ylmethoxy]-2,6-difluoro-benzamide

Prepared as per the method mentioned in Scheme 31.

Example 311 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-oxazol-2-ylmethoxy]-benzamide

To a solution of 3-[5-Bromo-4-(4-methoxy-phenyl)-oxazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.06 g, 0.13 mmol) in the 5 ml of acetic acid was added 50 mg of Zn dust. Reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and pH was adjusted to 8-9 with NaOH solution and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.02 g, 40%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 3.77 (s, 3H), 5.36 (s, 2H), 6.99 (d, J=8.40 Hz, 2H), 7.12 (m, 1H), 7.37 (m, 1H), 7.71 (d, J=8.40 Hz, 2H), 7.87 (br s, 1H), 8.15 (br s, 1H) and 8.56 (s, 1H). MS ES+ (361.24), HPLC (method I) Rt=15.41 min.

Example 312 2,6-Difluoro-3-[4-(4-hydroxy-phenyl)-oxazol-2-ylmethoxy]-benzamide

A solution of 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-oxazol-2-ylmethoxy]-benzamide (0.20 g, 0.55 mmol) in 10 ml of DCM was cooled to −78° C. followed by addition of BBr₃ (0.10 ml, 2.20 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO₃ (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.012 g, 6%). ¹H NMR (DMSO-d₆, 400 MHz): δ 5.35 (s, 2H), 6.82 (d, J=8.40 Hz, 2H), 7.14 (m, 1H), 7.38 (m, 1H), 7.58 (d, J=8.40 Hz, 2H), 7.87 (br s, 1H), 8.15 (br s, 1H), 8.47 (s, 1H) and 9.63 (s, 1H). MS ES+ (347.22), HPLC (method I) Rt=14.00 min.

4-(4-Methoxy-phenyl)-2-methyl-thiazole

A mixture of thioacetamide (16.0 g, 213 mmol) and 2-Bromo-1-(4-methoxy-phenyl)-ethanone (4.0 g, 17.5 mmol) was heated at 140° C. for 24 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 1% EtOAc-Hexane) to get the desired product (2.5 g, 69%).

5-Bromo-4-(4-methoxy-phenyl)-2-methyl-thiazole

To the solution of 5-Bromo-2-bromomethyl-4-(4-methoxy-phenyl)-thiazole (5.0 g, 24.3 mmol) in the 20 ml of CCl₄ was added NBS (4.32 g, 24.3 mmol) and AIBN (0.4 g, 2.43 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 1% ethyl acetate/hexane eluent to give the desired product (4.0 g, 58%).

4-(4-Methoxy-phenyl)-2-methyl-thiazole-5-carbonitrile

To a solution of 5-Bromo-4-(4-methoxy-phenyl)-2-methyl-thiazole (2.0 g, 7.0 mmol) in 15 ml of pyridine was added CuCN (3.10 g, 35.2 mmol) and the reaction mixture was heated to 150° C. in microwave for 2 h. After the completion of the reaction pH was adjusted to 3-4 with 1 N HCl solution and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 12% EtOAc-Hexane) to get the desired product (1.5 g, 92%) as a white solid.

4-(4-Methoxy-phenyl)-2-methyl-thiazole-5-carboxylic acid methyl ester

To a solution of 4-(4-Methoxy-phenyl)-2-methyl-thiazole-5-carbonitrile (0.50 g, 2.1 mmol) in 15 ml of methanol was passed dry HCl gas for 1 h at 0° C. The reaction mixture was stirred at 25° C. for 24 h. After the completion of the reaction mixture (TLC monitoring), The reaction mixture was evaporated to dryness under reduced pressure. Water (50 ml) was added and pH was adjusted to 7-8 with NaHCO₃ solution and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.25 g, 44%) as a white solid.

2-Bromomethyl-4-(4-methoxy-phenyl)-thiazole-5-carboxylic acid methyl ester

To the solution of 4-(4-Methoxy-phenyl)-2-methyl-thiazole-5-carboxylic acid methyl ester (0.25 g, 0.94 mmol) in the 20 ml of CCl₄ was added NBS (0.16 g, 0.94 mmol) and AlBN 0.015 g, 0.094 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 10% ethyl acetate/hexane as a eluent to give the desired product (0.078 g, 24%).

Example 313 2-(3-Carbamoyl-2,4-difluoro-phenoxymethyl)-4-(4-methoxy-phenyl)-thiazole-5-carboxylic acid methyl ester

To a solution of 2-Bromomethyl-4-(4-methoxy-phenyl)-thiazole-5-carboxylic acid methyl ester (0.05 g, 0.14 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.025 g, 0.14 mmol) and potassium carbonate (0.07 g, 0.50 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.025 g, 40%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.76 (s, 3H), 3.81 (s, 3H), 5.60 (s, 2H), 7.01 (d, J=8.40 Hz, 2H), 7.12 (m, 1H), 7.41 (m, 1H), 7.74 (d, J=8.40 Hz, 2H), 7.90 (br s, 1H) and 8.18 (br s, 1H). MS ES+ (435.06), HPLC (method I) Rt=15.86 min.

Trifluoromethanesulfonic acid cyclohex-1-enyl ester

To a solution of cyclohexanone (5.0 g, 51 mmol) in the 80 ml of DCM was added pyridine (4.48 ml, 56.0 mmol) and the resulting reaction mixture was cooled to −78° C. To the reaction mixture the solution of triflic anhydride (7.40 ml, 56.0 mmol) in 30 ml of DCM was added over the period of 1 h. Reaction mixture was stirred at 25° C. for 24 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was triturated with n-pentane and decanted the organic layer, dried (Na₂SO₄), filtered and concentrated to give the desired product (5.0 g, 42%).

Example 314 3-(5-Cyclohex-1-enyl-1H-inden-2-ylmethoxy)-2,6-difluoro-benzamide

To a solution of 2,6-Difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-inden-2-ylmethoxy]-benzamide (0.10 g, 0.20 mmol) in 3 ml of anhydrous DMF and water (1.5 ml) was added trifluoromethanesulfonic acid cyclohex-1-enyl ester (0.15 g, 0.60 mmol) and potassium phosphate (0.057 g, 0.20 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(triphenyl phosphine) palladium (II) (0.02 g, 0.03 mmol). The reaction mixture was heated at 80° C. for 1 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 45% EtOAc-Hexane) to get the desired product (0.017 g, 19%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 1.63 (m, 4H), 2.20 (m, 2H), 2.45 (m, 2H), 5.67 (s, 2H), 6.29 (m, 1H), 7.12 (m, 1H), 7.37 (m, 1H), 7.57 (m, 2H), 7.90 (br s, 1H), 8.03 (d, J=8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES+ (401.16), HPLC (method II) Rt=14.13 min.

Example 315 3-(5-Cyclohexyl-1H-inden-2-ylmethoxy)-2,6-difluoro-benzamide

To a solution of 3-(5-Cyclohex-1-enyl-1H-inden-2-ylmethoxy)-2,6-difluoro-benzamide (0.01 g, 0.25 mmol) in 5 ml of anhydrous methanol was added Pd—C (10%, 100 mg). The reaction mixture was stirred at 25° C. for 48 h under hydrogen atmosphere. The reaction mixture was filtered over the bed of celite and evaporated to dryness under reduced pressure to give the title compound as white solid (0.01 g, 10%). ¹H NMR (DMSO-d₆, 400 MHz); δ 1.40 (m, 6H), 1.72 (m, 4H), 2.63 (m, 1H), 5.66 (s, 2H), 7.09 (m, 1H), 7.35 (m, 2H), 7.83 (br s, 1H), 7.89 (d, J=8.40 Hz, 1H), 7.99 (d, J=8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES+ (403.33), HPLC (method II) Rt=18.76 min.

Trifluoro-methanesulfonic acid cyclopent-1-enyl ester

To a solution of cyclopentanone (5.0 g, 59 mmol) in the 80 ml of DCM was added pyridine (5.2 ml, 65.0 mmol) and the resulting reaction mixture was cooled to −78° C. To the reaction mixture the solution of triflic anhydride (9.2 ml, 65.0 mmol) in 30 ml of DCM was added over the period of 1 h. Reaction mixture was stirred at 25° C. for 24 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was triturated with n-pentane and decanted the organic layer, dried (Na₂SO₄), filtered and concentrated to give the desired product (2.4 g, 22%).

Example 316 3-(5-Cyclopent-2-enyl-1H-inden-2-ylmethoxy)-2,6-difluoro-benzamide

To a solution of 2,6-Difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-inden-2-ylmethoxy]-benzamide (0.25 g, 0.56 mmol) in 7 ml of anhydrous DMF and water (3.5 ml) was added trifluoromethanesulfonic acid cyclopent-1-enyl ester (0.37 g, 1.70 mmol) and potassium phosphate (0.14 g, 0.60 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(triphenyl phosphine) palladium (II) (0.05 g, 0.08 mmol). The reaction mixture was heated at 80° C. for 1 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 45% EtOAc-Hexane) to get the desired product (0.14 g, 65%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 1.22 (m, 2H), 2.01 (m, 2H), 2.88 (m, 2H), 5.68 (s, 2H), 6.43 (s, 1H), 7.01 (t, J=9.20 Hz, 1H), 7.37 (m, 1H), 7.67 (d, J=8.40 Hz, 1H), 7.89 (br s, 1H), 7.94 (s, 1H), 8.07 (d, J=8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES+ (387.15), HPLC (method II) Rt=13.74 min.

Example 317 3-(5-Cyclopentyl-1H-inden-2-ylmethoxy)-2,6-difluoro-benzamide

To a solution of 3-(5-Cyclopent-1-enyl-1H-inden-2-ylmethoxy)-2,6-difluoro-benzamide (0.05 g, 0.10 mmol) in 5 ml of anhydrous methanol was added Pd—C (10%, 100 mg). The reaction mixture was stirred at 25° C. for 48 h under hydrogen atmosphere. The reaction mixture was filtered over the bed of celite and evaporated to dryness under reduced pressure to give the title compound as white solid (0.005 g, 10%). ¹H NMR (DMSO-d₆, 400 MHz); δ 1.22 (m, 2H), 1.67 (m, 4H), 1.80 (m, 2H), 2.07 (m, 2H), 3.20 (m, 1H), 5.67 (s, 2H), 7.09 (m, 1H), 7.37 (m, 2H), 7.87 (m, 2H), 8.0 (m, 1H) and 8.18 (br s, 1H). MS ES+ (389.12), HPLC (method II) Rt=18.19 min.

Examples 318 to 333

Ethylthio-oxamate

To the solution of ethyl oxamate (10.0 g, 85.30 mmol) in 120 ml of toluene was added Lawesson's reagent (24.15 g, 59.7 mmol) and the reaction mixture was heated at 120° C. for 12 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (230-400 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.8 g, 16%).

4-(4-Trifluoromethyl-phenyl)-thiazole-2-carboxylic acid ethyl ester (Representative example)

To the solution of 2-Bromo-1-(4-trifluoromethyl-phenyl)-ethanone (0.50 g, 0.80 mmol) in 7 ml of ethanol was added ethyl thio-oxamate (0.15 g, 1.14 mmol). The reaction mixture was heated at 80° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was concentrated under reduced pressure, water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 2% EtOAc-Hexane) to get the desired product (0.21 g, 76%). The other derivatives were also prepared by the same general method.

[4-(4-Trifluoromethyl-phenyl)-thiazol-2-yl]-methanol

To an ice-cold suspension of LAH (0.056 g, 1.40 mmol) the 8 ml of anhydrous THF was added dropwise a solution of 4-(4-Trifluoromethyl-phenyl)-thiazole-2-carboxylic acid ethyl ester (0.21 g, 0.71 mmol) in the 5 ml of THF. The reaction mixture was stirred at 25° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), cooled the reaction mixture to 0° C. and quenched with 2.5 ml of water followed by the addition of 15% NaOH solution (2 mL) and finally 4 ml of water. The resulting solution was filtered through celite bed and the filtrate was concentrated under reduced pressure. Water (50 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to give the desired product (0.13 g, 70%). The other derivatives were also prepared by the same general method.

2-Bromomethyl-4-(4-trifluoromethyl-phenyl)-thiazole

To the solution of [4-(4-Trifluoromethyl-phenyl)-thiazol-2-yl]-methanol (0.13 g, 0.50 mmol) in 2 ml of toluene was added PBr₃ (0.072 ml, 0.752 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 1% EtOAc-Hexane) to get the desired product (0.04 g, 25%). The other derivatives were also prepared by the same general method.

4-Chloro-3-nitro-benzoic acid methyl ester

To a Solution of 4-chloro-3-nitrobenzoic acid (5.0 g, 24.81 mmol) in 50 ml of methanol was added H₂SO₄ (2 ml, 37.02 mmol) and the reaction mixture was heated at 70° C. for 5 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (50 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was, dried (Na₂SO₄), filtered and concentrated to give the desired product (5.04 g, 94%).

3-Amino-4-chloro-benzoic acid methyl ester

To a solution of 4-Chloro-3-nitro-benzoic acid methyl ester (5.0 g, 23.19 mmol) in 100 ml of ethanol was added SnCl₂.2H₂O (26.0 g, 115.96 mmol) and the reaction mixture was heated at 80° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (100 mL) was added, basified the reaction mixture with NaOH solution and extracted with hot EtOAc (3×250 mL).

The combined organics was dried over Na₂SO₄, filtered and concentrated to give the desired product (3.0 g, 69%).

3-(2-Benzyloxy-acetylamino)-4-chloro-benzoic acid methyl ester

A solution of carbonic acid monobenzyl ester (3.50 g, 21.0 mmol) in the 50 ml of DCM and 0.50 ml of DMF was cooled to −78° C. followed by addition of oxalyl chloride (11.79 ml, 105 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. After the completion of the reaction mixture (TLC monitoring), concentrated it to give 2-benzyloxyacetyl chloride (3.0 g, 96%). To an ice cold solution of 3-amino-4-chloro-benzoic acid methyl ester in 10 ml of DCM was added triethylamine (2.47 ml, 17.78 mmol) followed by addition of 2-benzyloxyacetyl chloride (3.0 g, 17.78 mmol) in 10 ml of DCM. The reaction mixture was stirred at 25° C. for 12 hr. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.70 g, 31%).

3-(2-Benzyloxy-thioacetylamino)-4-chloro-benzoic acid methyl ester

To the solution of 3-(2-Benzyloxy-acetylamino)-4-chloro-benzoic acid methyl ester (1.70 g, 5.10 mmol) in 20 ml of toluene was added Lawesson's reagent (1.03 g, 2.50 mmol) and the reaction mixture was heated at 120° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.20 g, 67%).

2-Benzyloxymethyl-benzothiazole-6-carboxylic acid methyl ester

To a solution of 3-(2-Benzyloxy-thioacetylamino)-4-chloro-benzoic acid methyl ester (1.20 g, 3.40 mmol) in the 8 ml of NMP was added NaH (0.12 g, 5.10 mmol) portion wise. The reaction mixture was heated at 160° C. for 3 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was poured into 150 ml of ice-cold water and extracted with ethyl acetate (3×150 mL). The combined organics was dried (Na₂SO₄), filtered and concentrated to give the desired product. (1.07 g, 56%).

2-Hydroxymethyl-benzothiazole-6-carboxylic acid methyl ester

A solution of 2-Benzyloxymethyl-benzothiazole-6-carboxylic acid methyl ester (0.10 g, 0.32 mmol) in 2 ml of DCM was cooled to −78° C. followed by addition of BBr₃ (0.06 ml, 0.64 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO₃ (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.08 g, Crude yield).

2-Bromomethyl-benzothiazole-6-carboxylic acid methyl ester

To a solution of 2-Hydroxymethyl-benzothiazole-6-carboxylic acid methyl ester (0.08 g, 0.40 mmol) in 5 ml of toluene and 1 ml of DMF was added PBr₃ (0.06 ml, 0.60 mmol). The reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.044 g, 36%).

Benzo[1,3]dioxole-5-carbonitrile

To a solution of 3,4 Dihydroxy benzonitrile (5.0 g, 37.0 mmol) in 20 ml of DMF was added dibromomethane (19.25 g, 110.0 mmol) and potassium carbonate (25.50 g, 184.90 mmol). The reaction mixture was heated at 120° C. for 2 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), reaction mixture was cooled to room temperature. Water (50 ml) was added to the reaction mixture and extracted the compound with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated to dryness under reduced pressure to give the title compound as yellow solid (5.16 g, 94.8%).

N-Hydroxy-benzo[1,3]dioxole-5-carboxamidine

To a solution of Benzo[1,3]dioxole-5-carbonitrile (5.0 g, 33.9 mmol) in EtOH (100 mL) was added hydroxylamine hydrochloride (4.68 g, 67.90 mmol) and NaOH (2.71 g, 67.9 mmol). The resulting reaction mixture was refluxed for 12 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated under reduced pressure and used as such for the next step (crude yield 4.8 g, 78.68%).

3-Benzo[1,3]dioxol-5-yl-5-bromomethyl-[1,2,4]oxadiazole

Bromoacetyl bromide (0.22 g, 1.10 mmol) was added to N-Hydroxy-benzo[1,3]dioxole-5-carboxamidine (0.40 g, 0.55 mmol) and K₂CO₃ (0.38 g, 0.78 mmol). The reaction mixture was heated at 100° C. for 15 min. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 5% EtOAc-Hexane) to get the desired product (0.05 g, 31%).

2-(4-Methoxy-phenyl)-thiazole-4-carboxylic acid ethyl ester

To an ice-cold solution of 4-methoxy-thiobenzamide (0.50 g, 2.98 mmol) in ethanol (25 ml) was added triethylamine (0.41 ml, 2.98 mmol) followed by dropwise addition of ethyl bromopyruvate (0.56 ml, 4.40 mmol). The reaction mixture was heated at 65° C. for 12 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure, water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 10% EtOAc-Hexane) to get the desired product (0.38 g, 48%).

[2-(4-Methoxy-phenyl)-thiazol-4-yl]-methanol

To an ice-cold suspension of LAH (0.08 g, 2.07 mmol) in 10 ml of anhydrous THF was added a solution of 2-(4-Methoxy-phenyl)-thiazole-4-carboxylic acid ethyl ester (0.26 g, 0.98 mmol) in 5 ml of THF. The reaction mixture was heated up to 60° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was cooled to 0° C., water (2.0 ml) was added followed by the addition of 15% NaOH solution (2 mL) and finally 4 ml of water. The resulting solution was filtered through celite bed and concentrated under reduced pressure; water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to give the desired product (0.14 g, 64%).

4-Bromomethyl-2-(4-methoxy-phenyl)-thiazole

To a solution of [2-(4-Methoxy-phenyl)-thiazol-4-yl]-methanol (0.12 g, 0.50 mmol) in 3 ml of toluene was added PBr₃ (0.078 ml, 0.813 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.13 g, 84%).

3-(4-Chloro-phenyl)-5-ethyl-[1,2,4]oxadiazole

Propionic anhydride (0.75 mL, 5.79 mmol) was added to 4-Chloro-N-hydroxy-benzamide (0.50 g, 2.89 mmol) and K₂CO₃ (2.0 g, 14.48 mmol). The reaction mixture was heated at 100° C. for 30 min. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was cooled to 0° C., added water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 5% EtOAc-Hexane) to get the desired product (0.29 g, 48%).

5-(1-Bromo-ethyl)-3-(4-chloro-phenyl)-[1,2,4]oxadiazole

To a solution of 3-(4-Chloro-phenyl)-5-ethyl-[1,2,4]oxadiazole (0.29 g, 1.38 mmol) in CCl₄ (10 mL) was added NBS (0.24 g, 1.38 mmol) and AIBN (0.02 g, 0.0001 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 1% ethyl acetate/hexane as eluent to give the desired product (0.12 g, 30%).

4-Bromomethyl-5-methyl-2-phenyl-2H-[1,2,3]triazole

To a solution of (5-Methyl-2-phenyl-2H-[1,2,3]triazol-4-yl)-methanol (0.25 g, 1.30 mmol) in 10 ml of toluene was added PBr₃ (0.53 g, 1.90 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.30 g, 90%) as a yellow solid.

Thiazole-2-carbonitrile

To a solution of 2-bromothiazole (1.0 g, 6.09 mmol) in 4 ml of pyridine was added CuCN (1.09 g, 12.19 mmol). The reaction mixture was heated to 150° C. for 3 h. After the completion of the reaction, pH was adjusted to 3-4 with 1N HCl solution and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.42 g, 63%).

N-Hydroxy-thiazole-2-carboxamidine

To a solution of thiazole-2-carbonitrile (0.42 g, 3.80 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (0.53 g, 7.60 mmol) and pyridine (0.27 g, 3.40 mmol). The resulting reaction mixture was refluxed for 15 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated under reduced pressure and used as such for the next step (crude yield 0.50 g, 91% crude yield).

5-Chloromethyl-3-thiazol-2-yl-[1,2,4]oxadiazole

Chloroacetyl Chloride (5.0 mL, 44.5 mmol) was added to N-Hydroxy-thiazole-2-carboxamidine (0.50 g, 3.49 mmol) and K₂CO₃ (1.0 g, 7.20 mmol). The reaction mixture was heated at 100° C. for 15 min. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (0.18 g, 25%) as a white solid.

N-(4-Phenoxy-phenyl)-acetamide

To an ice-cold solution of 4-phenoxy-phenylamine (1.0 g, 5.39 mmol) in 10 ml of DCM was added triethylamine (0.90 ml, 5.93 mmol) followed by acetyl chloride (0.50 g, 6.47 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), water was added extracted with DCM (3×50 mL). The combined organics was dried (Na₂SO₄), filtered and concentrated to get the desired product (1.20 g, crude yield).

N-(4-Phenoxy-phenyl)-thioacetamide

To a solution of N-(4-phenoxy-phenyl)-acetamide (1.20 g, 5.28 mmol) in 10 ml of toluene was added Lawesson's reagent (1.50 g, 3.70 mmol). The reaction mixture was heated at 120° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (0.78 g, 60.7%).

2-Methyl-6-phenoxy-benzothiazole

To an ice-cold solution of N-(4-phenoxy-phenyl)-thioacetamide (0.78 g, 3.20 mmol) in 10 ml of DCM was added Br₂ (0.32 ml, 6.40 mmol) dropwise. The reaction mixture was heated at 45° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated under reduced pressure. The residue was basified with NH₄OH solution and extracted with ethyl acetate. The combined organics were, dried, (Na₂SO₄), filtered and concentrated. The residue was purified by column chromatography on silica (230-400 M) using ethyl acetate/hexane (3:97) as the eluent to provide the title compound (0.08 g, 10.3%).

2-Bromomethyl-6-phenoxy-benzothiazole

To a solution of 2-methyl-6-phenoxy-benzothiazole (0.06 g, 0.24 mmol) in 5 ml of CCl₄ was added NBS (0.039 g, 0.22 mmol) and AIBN (0.004 g, 0.024 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400M) using 1% ethyl acetate/hexane eluent to give the desired product (0.005 g, 6.3%).

7-Bromomethyl-quinoline

To a solution of 7-methylquinoline (0.10 g, 0.70 mmol) in 5 ml of CCl₄ was added NBS (0.14 g, 0.77 mmol) and AIBN (0.025 g, 0.15 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400M) using 1% ethyl acetate/hexane eluent to give the desired product (0.090 g, 58%).

Examples 318-333 (Table R)

The compounds of Examples 318-333 were synthesised according to the following general procedure: To a solution of reactant (A) in anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (B) and potassium carbonate (C). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica using ethyl acetate/hexane as the eluent to provide the product compound.

TABLE R Example 318 319 Product 2,6-Difluoro-3-[4-(4-fluoro-phenyl)- 2,6-Difluoro-3-[4-(4-trifluoromethyl- thiazol-2-ylmethoxy]-benzamide phenyl)-thiazol-2-ylmethoxy]- benzamide Reaction scheme

Reactant (A) 2-Bromomethyl-4-(4-fluoro-phenyl)- 2-Bromomethyl-4-(4-trifluoromethyl- thiazole phenyl)-thiazole Quantities A; B; 0.30 g, 1.10 mmol; 0.17 g, 0.99 mmol; 0.04 g, 0.01 mmol; 0.02 g, 0.01 C; volume DMF 0.52 g, 3.5 mmol; 2 ml mmol; 0.05 g, 0.30 mmol; 2 ml Ethyl acetate: 50:50 50:50 hexane ratio Silica 230-400M 60-120M Yield 0.035 g, 8%, white solid 0.017 g, 33%, white solid ¹H NMR δ 5.58 (s, 2H), 7.15 (d, J = 8.80 Hz, 1H), δ 5.61 (s, 2H), 7.15 (t, J = 8.80 Hz, (DMSO-d₆, 400 7.32 (m, 2H), 7.44 (m, 1H), 7.89 (br s, 1H), 7.45 (m, 1H), 7.84 (d, J = 8.40 MHz) 1H), 8.03 (m, 2H) and 8.18 (s, 2H) Hz, 2H), 7.89 (br s, 1H), 8.20 (m, 3H) and 8.43 (s, 1H) MS-ES+ 364.97 415.23 HPLC method 9, 16.50 8, 16.96 no., Rt (min) Example 320 321 Product 2,6-Difluoro-3-[4-(4-trifluoromethoxy-phenyl)- 2-(3-Carbamoyl-2,4-difluoro-phenoxymethyl)- thiazol-2-ylmethoxy]-benzamide benzothiazole-6-carboxylic acid methyl ester Reaction scheme

Reactant (A) 2-Bromomethyl-4-(4-trifluoromethoxy-phenyl)- 2-Bromomethyl-benzothiazole-6-carboxylic thiazole acid methyl ester Quantities A; B; 0.14 g, 0.40 mmol; 0.07 g, 0.04 mmol; 0.16 g, 1.2 1.40 g, 4.89 mmol; 0.76 g, 4.40 mmol; 2.37 g, C; volume DMF mmol; 2 ml 17.12 mmol; 15 ml Ethyl acetate: 50:50 50:50 hexane ratio Silica 230-400M 60-120M Yield 0.005 g, 2%, white solid 1.20 g, 64.8%, white solid ¹H NMR δ 5.59 (s, 2H), 7.12 (m, 1H), 7.40 (m, 1H), 7.46 δ 3.91 (s, 3H), 5.74 (s, 2H), 7.12 (m, 1H), 7.40 (DMSO-d₆, 400 (d, J = 8.40 Hz, 2H), 7.87 (br s, 1H), 8.09 (d, J = (m, 1H), 7.90 (br s, 1H), 8.0 (d, J = 8.40 Hz, MHz) 8.80 Hz, 2H), 8.16 (br s, 1H) and 8.27 (s, 1H) 1H), 8.18 (br s, 1H), 8.32 (d, J = 8.40 Hz, 1H) and 8.52 (s, 1H) MS-ES+ 431.28 379.11 HPLC method 8, 17.10 9, 15.22 no., Rt (min) Example 322 323 Product 3-(3-Benzo[1,3]dioxol-5-yl-[1,2,4]oxadiazol-5- 2,6-Difluoro-3-[2-(4-methoxy-phenyl)-thiazol- ylmethoxy)-2,6-difluoro-benzamide 4-ylmethoxy]-benzamide Reaction scheme

Reactant (A) 3-Benzo [1,3]dioxol-5-yl-5-bromomethyl- 4-Bromomethyl-2-(4-methoxy-phenyl)-thiazole [1,2,4]oxadiazole Quantities A; B; 0.30 g, 1.06 mmol; 0.18 g, 1.06 mmol; 0.312 g, 0.11 g, 0.40 mmol; 0.063 g, 0.36 mmol; 0.19 C; volume DMF 3.70 mmol; 2 ml g, 1.40 mmol; 2 ml Ethyl acetate: 50:50 50:50 hexane ratio Silica 60-120M 60-120M Yield 0.13 g, 32.67%, white solid 0.035 g, 23%, white solid ¹H NMR δ 5.66 (s, 2H), 6.14 (s, 2H), 7.10 (m, 2H), 7.38 δ 3.82 (s, 3H), 5.27 (s, 2H), 7.07 (d, J = 8.80 (DMSO-d₆, 400 (m, 1H), 7.45 (s, 1H), 7.56 (m, 1H), 7.90 (br s, Hz, 2H), 7.12 (m, 1H), 7.42 (m, 1H), 7.71 (s, MHz) 1H) and 8.18 (br s, 1H) 1H), 7.89 (m, 3H) and 8.14 (br s, 1H) MS-ES+ 376.16 377.21 HPLC method 8, 15.43 8, 15.93 no., Rt (min) Example 324 325 Product 3-{1-[3-(4-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]- 2,6-Difluoro-3-(5-methyl-2-phenyl-2H- ethoxy}-2,6-difluoro-benzamide [1,2,3]triazol-4-ylmethoxy)-benzamide Reaction scheme

Reactant (A) 5-(1-Bromo-ethyl)-3-(4-chloro-phenyl)-[1,2,4] 4-Bromomethyl-5-methyl-2-phenyl-2H- oxadiazole [1,2,3]triazole Quantities A; B; 0.11 g, 0.38 mmol; 0.05 g, 0.34 mmol; 0.18 g, 0.23 g, 0.90 mmol; 0.15 g, 0.90 mmol; 0.44 g, C; volume DMF 1.33 mmol; 2 ml 3.1 mmol; 5 ml Ethyl acetate: 50:50 50:50 hexane ratio Silica 60-120M 60-120M Yield 0.06 g, 41%, white solid 0.03 g, 9.5%, white solid ¹H NMR δ 1.81 (d, J = 6.80 Hz, 3H), 5.98 (q, J = 6.80 Hz, δ 2.39 (s, 3H), 5.34 (s, 2H), 7.12 (m, 1H), 7.40 (DMSO-d₆, 400 1H), 7.08 (m, 1H), 7.40 (m, 1H), 7.66 (d, J = 8.40 (m, 2H), 7.55 (m, 2H), 7.86 (br s, 1H), 7.96 (d, MHz) Hz, 2H), 7.88 (br s, 1H), 8.02 (d, J = 8.40 Hz, 2H) J = 8.0 Hz, 2H) and 8.14 (br s, 1H) and 8.16 (br s, 1H) MS-ES+ 380.09 345.20 HPLC method 8, 16.81 8, 16.18 no., Rt (min) Example 326 327 Product 2,6-Difluoro-3-(3-thiazol-2-yl-[1,2,4]oxadiazol-5- 2,6-Difluoro-3-(5-phenoxy-benzothiazol-2- ylmethoxy)-benzamide ylmethoxy)-benzamide Reaction scheme

Reactant (A) 5-Chloromethyl-3-thiazol-2-yl-[1,2,4]oxadiazole 2-bromomethyl-5-phenoxy-benzothiazole Quantities A; B; 0.18 g, 0.89 mmol; 0.014 g, 0.89 mmol; 0.36 g, 0.005 g, 0.015 mmol; 0.003 g, 0.015 mmol; C; volume DMF 2.68 mmol; 2 ml 0.008 g, 0.054 mmol; 1 ml Ethyl acetate: 45:55 50:50 hexane ratio Silica 230-400M 60-120M Yield 0.10 g, 33%, lemon yellow solid 0.001 g, 16%, white solid ¹H NMR δ 5.73 (s, 2H), 7.11-7.16 (m, 1H), 7.37-7.43 (m, δ 5.76 (s, 2H), 7.03-7.23 (m, 5H), 7.35-7.43 (DMSO-d₆, 400 1H), 7.90 (br s, 1H) and 8.16-8.19 (m, 3H) (m, 3H), 7.56 (m, 1H), 7.90 (br s, 1H) and MHz) 8.14-8.18 (m, 2H) MS-ES+ 339.20 413.24 HPLC method 8, 13.99 n/a no., Rt (min) Example 328 329 Product 3-[3-(4-Difluoromethoxy-3-methoxy-phenyl)- 3-[3-(4-Chloro-3-nitro-phenyl)- [1,2,4]oxadiazol-5-ylmethoxy]-2,6-difluoro- [1,2,4]oxadiazol-5-ylmethoxy]-2,6-difluoro- benzamide benzamide Reaction scheme

Reactant (A) 5-chloromethyl-3-(4-difluoromethoxy-3-methoxy- 5-chloromethyl-3-(4-chloro-3-nitro-phenyl)- phenyl)-[1,2,4]oxadiazole [1,2,4]oxadiazole Quantities A; B; 0.10 g, 0.34 mmol; 0.059 g, 0.34 mmol; 0.16 g, 0.15 g, 0.54 mmol; 0.085 g, 0.49 mmol; 0.26 C; volume DMF 1.20 mmol; 2 ml g, 1.90 mmol; 2 ml Ethyl acetate: 50:50 50:50 hexane ratio Silica 60-120M 60-120M Yield 0.035 g, 23%, white solid 0.06 g, 26%, white solid ¹H NMR δ 3.92 (s, 3H), 5.70 (s, 2H), 7.14 (m, 1H), 7.22 (s, δ 5.76 (s, 2H), 7.13 (m, 1H), 7.40 (m, 1H), (DMSO-d₆, 400 1H), 7.40 (m, 2H), 7.65 (m, 2H), 7.91 (br s, 1H) 7.90 (br s, 1H), 8.01 (d, J = 8.40 Hz, 1H), 8.18 MHz) and 8.19 (br s, 1H) (br s, 1H), 8.29 (m, 1H) and 8.61 (s, 1H) MS-ES+ 428.27 411.15 HPLC method 8, 15.96 8, 16.20 no., Rt (min) Example 330 331 Product 2,6-Difluoro-3-(quinolin-7-ylmethoxy)-benzamide 3-(3-Chloro-benzyloxy)-2,6-difluoro- benzamide Reaction scheme

Reactant (A) 7-bromomethylquinoline 1-bromomethy-3-chlorobenzene Quantities A; B; 0.90 g, 0.40 mmol; 0.071 g, 0.40 mmol; 0.19 g, 0.20 g, 0.98 mmol; 0.17 g, 0.98 mmol; 0.47 g, C; volume DMF 1.40 mmol; 2 ml 3.45 mmol; 2 ml Ethyl acetate: 50:50 40:60 hexane ratio Silica 60-120M 60-120M Yield 0.012 g, 10%, white solid 0.14 g, 48%, white solid ¹H NMR δ 5.44 (s, 2H), 7.07 (m, 1H), 7.33 (m, 1H), 7.54 δ 5.19 (s, 2H), 7.07 (t, J = 9.20 Hz, 1H), 7.27 (DMSO-d₆, 400 (m, 1H), 7.66 (m, 1H), 7.86 (br s, 1H), 8.04 (d, J = m, 1H), 7.42 (m, 3H), 7.51 (s, 1H), 7.86 (br s, MHz) 8.40 Hz, 1H), 8.08 (s, 1H), 8.15 (br s, 1H), 8.37 1H) and 8.14 (br s, 1H) (d, J = 8.40 Hz, 1H) and 8.91 (m, 1H) MS-ES+ 315.02 298.05 HPLC method 9, 12.46 9, 16.37 no., Rt (min) Example 332 333 Product 2,6-Difluoro-3-(3-nitro-benzyloxy)-benzamide 2,6-Difluoro-3-[2-(5-methyl-2-p-tolyl-oxazol-4- yl)-ethoxy]-benzamide Reaction scheme

Reactant (A) 1-Bromomethyl-3-nitro-benzene 4-(2-Bromo-ethyl)-5-methyl-2-p-tolyl-oxazole Quantities A; B; 0.216 g, 1.0 mmol; 0.17 g, 1.0 mmol; 0.48 g, 3.5 0.10 g, 0.35 mmol; 0.061 g, 0.35 mmol; 0.17 C; volume DMF mmol; 2 ml g, 1.24 mmol; 2 ml Ethyl acetate: 50:50 50:50 hexane ratio Silica 60-120M 60-120M Yield 0.11 g, 35%, white solid 0.022 g, 16%, white solid ¹H NMR δ 5.34 (s, 2H), 7.07 (m, 1H), 7.30 (m, 1H), 7.72 (t, δ 2.34 (br s, 6H), 2.93 (t, J = 6.40 Hz, 2H), (DMSO-d₆, 400 J = 8.0 Hz, 1H), 7.90 (m, 2H), 8.15 (br s, 1H), 4.26 (t, J 6.40 Hz, 2H), 7.04 (t, J = 8.80 Hz, MHz) 8.23 (d, J = 8.40 Hz, 1H) and 8.33 (br s, 1H) 1H), 7.21-7.31 (m, 3H), 7.80 (d, J = 8.0 Hz, 2H), 7.84 (br s, 1H) and 8.11 (br s, 1H) MS-ES+ 309.23 373.21 HPLC method 9, 15.32 8, 16.61 no., Rt (min)

4-(3-Methoxy-phenyl)-2-methyl-thiazole

A mixture of thioacetamide (8.0 g, 106.0 mmol) and 2-bromo-1-(3-methoxy-phenyl)-ethanone (2.0 g, 8.81 mmol) was heated at 140° C. for 6 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (50 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 2% EtOAc-Hexane) to get the desired product (1.5 g, 83%).

5-Bromo-2-bromomethyl-4-(3-methoxy-phenyl)-thiazole

To a solution 4-(3-methoxy-phenyl)-2-methyl-thiazole (1.50, 7.30 mmol) in the 20 ml of CCl₄ was added NBS (2.60 g, 14.60 mmol) and AIBN (0.12 g, 0.73 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 2% ethyl acetate/hexane as a eluent to give the desired product (1.20 g, 45%).

3-[5-Bromo-4-(3-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide

To a solution of 5-Bromo-2-bromomethyl-4-(3-methoxy-phenyl)-thiazole (0.80 g, 2.20 mmol) in 5 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.38 g, 2.20 mmol) and potassium carbonate (1.06 g, 7.70 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.50 g, 49%).

2,6-Difluoro-3-[4-(3-methoxy-phenyl)-thiazol-2-ylmethoxy]-benzamide

To the solution of 3-[5-bromo-4-(3-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.50 g, 1.10 mmol) in the 10 ml of acetic acid was added Zn dust (0.50 g, w/w). The reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), water (50 mL) was added and pH was adjusted to 8-9 with NaOH solution and extracted with ethyl acetate (3×100 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated to get the desired product (0.22 g, 53%).

Example 334 2,6-Difluoro-3-[4-(3-hydroxy-phenyl)-thiazol-2-ylmethoxy]-benzamide

A solution of 2,6-Difluoro-3-[4-(3-methoxy-phenyl)-thiazol-2-ylmethoxy]-benzamide (0.20 g, 0.53 mmol) in 15 ml of DCM was cooled to −78° C. followed by addition of BBr₃ (0.20 ml, 2.14 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO₃ (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na₂SO₄), filtered and concentrated. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.065 g, 33%). ¹H NMR (DMSO-d₆, 400 MHz): δ 5.60 (s, 2H), 6.74 (m, 1H), 7.10 (m, 1H), 7.24 (m, 1H), 7.37-7.45 (m, 3H), 7.90 (br s, 1H), 8.10 (s, 1H), 8.17 (br s, 1H) and 9.55 (s, 1H). MS ES+ (362.99), HPLC (method II) Rt=14.95 min.

Minimum Inhibitory Concentration (MIC) Testing

Compounds of this invention were tested for antimicrobial activity by susceptibility testing in liquid media. MICs for compounds against each strain were determined by a broth microdilution method according to the National Committee for Clinical Laboratory Standards (NCCLS) guidelines. (NCCLS. 2000. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically—fifth edition. Approved standard M7-A5. NCCLS, Wayne, Pa.)

Briefly, test compounds are prepared in 100 μl of 1.6% DMSO solution in multiwell plates. Several bacterial colonies from a freshly streaked plate are transferred to an appropriate rich broth, such as Mueller Hinton. The cell suspension is adjusted to an optical density of 0.09 and further diluted 1:100 with warm 2× broth. This cell suspension is dispensed into the wells containing compound solution so that the final volume is 200 μl. The plates are incubated overnight (16-20 hours) at 37° C. and turbidity is scored by eye and quantified spectrophotometrically. The MIC is defined as the lowest concentration inhibiting visible growth.

Compounds of the current invention were found to have antimicrobial activity in the MIC assay described above.

Results

Table 1 shows the Minimal Inhibitory Concentration (MIC) of the Examples against Bacillus subtilis 168_(CA). Activities were scored as ‘A’ if the MIC was ≦8 micrograms/ml, ‘B’ if the MIC was 16 to 64 micrograms/ml and ‘C’ if the MIC was greater than 64 micrograms/ml.

TABLE 1 Bacillus subtilis MICs Example Activity 1 A 2 C 3 C 4 C 5 B 6 C 7 C 8 B 9 C 10 A 11 C 12 B 13 B 14 B 15 B 16 C 17 B 18 C 19 A 20 A 21 B 22 B 23 B 24 A 25 C 26 C 27 C 28 A 29 B 30 C 31 B 32 A 33 C 34 B 35 B 36 A 37 C 38 A 39 B 40 A 41 B 42 B 43 B 44 A 45 A 46 A 47 A 48 A 49 A 50 A 51 A 52 A 53 C 54 B 55 A 56 A 57 A 58 A 59 A 60 B 61 A 62 A 63 A 64 A 65 A 66 A 67 A 68 A 69 A 70 A 71 A 72 B 73 A 74 A 75 A 76 A 77 B 78 A 79 B 80 B 81 A 82 A 83 A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94 A 95 B 96 B 97 A 98 A 99 A 100 A 101 B 102 A 103 A 104 A 105 A 106 A 107 A 108 B 109 A 110 A 111 A 112 A 113 A 114 A 115 B 116 B 117 A 118 A 119 A 120 A 121 A 122 A 123 A 124 A 125 A 126 A 127 A 128 A 129 C 130 A 131 B 132 A 133 A 134 B 135 A 136 A 137 B 138 C 139 A 140 C 141 A 142 A 143 C 144 C 145 B 146 A 147 B 148 A 149 A 150 A 151 A 152 B 153 A 154 A 155 A 156 A 157 A 158 A 159 A 160 A 161 A 162 A 163 A 164 A 165 A 166 C 167 B 168 C 169 C 170 C 171 B 172 C 173 C 174 B 175 A 176 A 177 A 178 B 179 C 180 A 181 A 182 C 183 B 184 B 185 C 186 A 187 B 188 B 189 C 190 B 191 B 192 C 193 B 194 C 195 A 196 A 197 B 198 B 199 C 200 A 201 A 202 A 203 C 204 B 205 A 206 A 207 A 208 A 209 B 210 A 211 A 212 A 213 A 214 B 215 A 216 A 217 A 218 A 219 A 220 A 221 A 222 A 223 A 224 B 225 C 226 B 227 A 228 A 229 A 230 A 231 A 232 B 233 A 234 A 235 A 236 A 237 B 238 B 239 B 240 A 241 A 242 A 243 A 244 245 A 246 A 247 A 248 A 249 A 250 A 251 B 252 A 253 B 254 A 255 A 256 A 257 A 258 A 259 A 260 A 261 B 262 B 263 A 264 B 265 A 266 B 267 A 268 A 269 A 270 A 271 A 272 A 273 A 274 A 275 B 276 A 277 A 278 A 279 A 280 A 281 A 282 A 283 A 284 A 285 A 286 A 287 A 288 A 289 A 290 A 291 A 292 A 293 A 294 A 295 A 296 A 297 A 298 A 299 A 301 A 302 A 303 A 304 A 305 A 306 A 307 A 308 A 309 A 310 A 311 A 312 B 313 A 314 A 315 A 316 A 317 A 318 A 319 A 320 A 321 A 322 A 323 A 324 A 325 A 326 B 327 A 328 A 329 A 330 B 331 A 332 B 333 A 334 B

Some of the compounds of the Examples were also tested for activity against the pathogenic organism Staphylococcus aureus ATCC29213. Table 2 shows the MICs of the Examples against Staphylococcus aureus. Activities were again scored as ‘A’ if the MIC was ≦8 micrograms/ml, ‘B’ if the MIC was 16 to 64 micrograms/ml and ‘C’ if the MIC was greater than 64 micrograms/ml.

TABLE 2 Staphylococcus aureus MICs Example Activity 1 A 5 B 8 B 12 A 15 B 17 B 18 C 19 A 24 A 26 C 27 C 28 C 29 B 30 C 31 B 32 B 36 C 39 B 40 A 41 B 42 B 43 B 45 A 46 A 47 B 49 A 51 B 52 A 53 C 54 B 55 A 56 A 57 B 58 A 59 B 60 B 61 A 62 A 64 A 65 A 66 A 67 A 68 A 69 A 70 A 71 A 72 B 73 A 74 A 75 A 76 A 77 B 78 A 79 B 80 B 81 A 82 A 83 B 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 93 B 94 A 95 C 98 A 99 A 100 A 101 B 102 A 103 A 104 A 105 A 106 A 107 A 108 B 109 B 111 A 114 A 115 A 116 B 117 A 118 A 119 A 120 A 121 A 122 A 123 A 124 A 125 A 126 A 127 A 128 B 129 B 130 A 132 A 133 A 134 B 135 A 136 A 137 B 138 C 139 A 140 A 141 A 143 A 144 C 145 C 146 B 147 B 148 A 149 B 150 B 151 B 152 B 153 A 155 A 156 A 157 A 158 A 159 A 161 A 162 A 163 A 164 A 165 A 166 C 167 B 168 C 169 C 170 C 171 B 172 C 173 C 174 B 175 A 176 B 177 A 178 B 179 C 180 B 181 B 182 C 183 B 184 B 185 C 186 B 187 B 188 B 189 C 190 B 191 B 192 C 193 B 194 C 195 B 196 B 197 B 200 B 201 B 202 B 204 B 205 A 206 C 207 B 208 A 209 C 210 A 211 B 212 B 213 B 214 B 215 A 216 A 217 A 218 A 219 A 220 A 221 A 222 A 223 A 224 C 225 C 226 B 227 A 228 B 229 A 230 A 231 A 232 A 233 A 235 A 236 A 237 B 239 B 240 A 241 A 242 A 243 A 245 A 246 A 247 A 248 A 249 A 250 A 251 B 252 A 256 B 257 A 260 A 262 B 263 B 265 B 266 B 267 A 268 B 269 A 270 A 271 A 272 A 273 A 274 A 275 B 276 A 277 A 278 A 279 A 280 A 281 A 282 A 283 A 284 A 285 A 286 A 287 A 288 A 289 A 290 A 291 A 292 A 293 A 294 A 295 A 296 A 297 A 298 A 299 A 300 B 301 B 302 A 303 A 304 A 305 A 306 A 307 A 308 B 309 A 310 B 311 A 312 A 313 A 314 B 315 A 316 A 317 A 318 A 319 A 320 A 321 A 322 A 323 A 324 A 325 B 326 B 327 A 331 B 333 A 334 A

Some of the Examples were also tested for activity against other bacterial species. Table 3 shows the MICs of the Examples against various bacterial species. Activities were again scored as ‘A’ if the MIC was ≦8 micrograms/ml, ‘B’ if the MIC was 16 to 64 micrograms/ml and ‘C’ if the MIC was greater than 64 micrograms/ml.

TABLE 3 MICs against various bacteria Activity Bacillus cereus Staphylococcus Staphylococcus Staphylococcus ATCC epidermidis haemolyticus saprophyticus Example 14579 ATCC 12228 ATCC 29970 ATCC 15305 46 A 84 A 87 A 88 A 175 A 215 A 177 A 217 A A A 218 A A A A 236 A A 111 A 208 A A 114 A A 106 A A A A 246 A A A A 242 A A 135 A 139 A A 287 A 271 A 282 A 311 A

Some of the Examples were also tested for activity against staphylococcal clinical isolates. Table 4 shows the MICs of the examples against various clinical isolates. Activities were again scored as ‘A’ if the MIC was ≦8 micrograms/ml, ‘B’ if the MIC was 16 to 64 micrograms/ml and ‘C’ if the MIC was greater than 64 micrograms/ml.

TABLE 4 MICs against clinical isolates Example - Oxacillin Antibiotic Other Activity Organism No. (S/R¹) Susceptibility² Information 217 236 218 S. aureus 0100 S ATCC 29213 A A A 1134 S Hospital A A A 753 S Hospital A A A 1662 S Hospital A A A 1015 R Van-S, LZD-S Hospital A A A 1135 R Van-S, LZD-S Hospital A A A 2012 R Van-I, LZD-S Hospital A A A 2018 R Van-I, LZD-S Hospital A A A 1651 R Van-S, LZD-R Hospital A A A (G2576T, G) 1652 R Van-S, LZD-R Hospital A A A (T2500T, A) 1725 R Van-S, LZD-R Hospital A A A (G2576T) 2011 R Tet-R, MI-S Hospital (tetK) A A A 757 R Tet-R, MI-R Hospital A A A (tetM) 1729 R Tet-R, MI-R Hospital A A A 2147 R CC-S, SXT-S Community A A A 2142 R CC-S, SXT-S Community A A A 2158 R CC-R, Doxy-I Community A A A 2150 R CC-R, SXT-S Community A A A 2149 R CC-R (iMLS), Community A A A SXT-S 2175 R TMP-R Community A A A 2143 R Rif-R Community A A A S. epidermidis 835 S A A A 1139 S A A A 831 R A A A 1142 R A A A 1144 R A A A ¹S, susceptible; I, intermediate; R, resistant ²Van, vancomycin; LZD, linezolid; Tet, tetracycline; MI, minocycline; CC, clindamycin, SXT, trimethoprim/sulfamethoxazole; Doxy, doxycycline; iMLS, inducible macrolide-lincosamide-streptogramin B resistance; TMP, trimethoprim; Rif, rifampin

Some of the Examples were also tested for activity in a mouse Staphylococcus aureus septicaemia model of infection. Table 5 shows the survival at day 7 of infected mice treated with a single intraperitoneal dose of 100 mg/kg of each Example at 1 hour after intraperitoneal inoculation with a lethal dose of Staphylococcus aureus.

TABLE 5 Murine Survival Example Percent survival Vehicle control 0 218 100 106 100 241 100 247 100 246 100 

1. A compound of the formula I or a salt, thereof 